Published online Aug 26, 2014. doi: 10.4330/wjc.v6.i8.692
Revised: April 29, 2014
Accepted: June 27, 2014
Published online: August 26, 2014
A number of disparate diseases can lead to pulmonary hypertension (PH), a serious disorder with a high morbidity and mortality rate. Recent studies suggest that the associated metabolic dysregulation may be an important factor adversely impacting the prognosis of PH. Furthermore, metabolic syndrome is associated with vascular diseases including PH. Inflammation plays a significant role both in PH and metabolic syndrome. Adipose tissue modulates lipid and glucose metabolism, and also produces pro- and anti-inflammatory adipokines that modulate vascular function and angiogenesis, suggesting a close functional relationship between the adipose tissue and the vasculature. Both caveolin-1, a cell membrane scaffolding protein and peroxisome proliferator-activated receptor (PPAR) γ, a ligand-activated transcription factor are abundantly expressed in the endothelial cells and adipocytes. Both caveolin-1 and PPARγ modulate proliferative and anti-apoptotic pathways, cell migration, inflammation, vascular homeostasis, and participate in lipid transport, triacylglyceride synthesis and glucose metabolism. Caveolin-1 and PPARγ regulate the production of adipokines and in turn are modulated by them. This review article summarizes the roles and inter-relationships of caveolin-1, PPARγ and adipokines in PH and metabolic syndrome.
Core tip: Pulmonary hypertension (PH) is a devastating disease with a high morbidity and mortality rate. Recent studies indicate that the metabolic alterations that occur during the course of PH have a negative effect. Importantly, PH has been observed in patients with metabolic syndrome. Caveolin-1, a membrane protein and peroxisome proliferator-activated receptor γ, a ligand activated transcription factor are abundantly expressed in vascular cells and adipocytes. They play a significant role in maintaining vascular health, and participate in glucose and lipid metabolism. Furthermore, the proximity of vasculature and adipose tissue facilitates reciprocal influence during health and disease.
- Citation: Mathew R. Pulmonary hypertension and metabolic syndrome: Possible connection, PPARγ and Caveolin-1. World J Cardiol 2014; 6(8): 692-705
- URL: https://www.wjgnet.com/1949-8462/full/v6/i8/692.htm
- DOI: https://dx.doi.org/10.4330/wjc.v6.i8.692
Chronic inflammation plays a significant role in metabolic syndrome and vascular diseases including pulmonary hypertension (PH). Adipose tissue not only functions as an energy store, but also as an endocrine system producing bioactive substances that influence metabolic and vascular homeostasis. Adipocytes play an important role in regulating inflammatory response. Obesity is associated with chronic inflammation, activation of proinflammatory cytokines, and with the infiltration of adipose tissue with macrophages and lymphocytes[1,2]. Interestingly, increased plasma and lung levels of pro-inflammatory cytokines[3,4] and perivascular infiltration of inflammatory cells and neo-lymphogenesis in peri-bronchial areas[5-7] have been reported in human and experimental forms of PH. Both caveolin-1, a plasma membrane protein and peroxisome proliferator-activated receptor (PPAR) γ, a ligand-activated transcription factor belonging to the nuclear hormone receptor family are expressed abundantly in adipose and vascular tissues. They modulate inflammation, vascular contractility, cell proliferation, cell cycle progression, and play a significant role in maintaining vascular health, and participate in glucose and lipid metabolism[8-11]. Furthermore, perivascular adipose tissue (PVAT) has been shown to modulate vascular function. Under normal circumstances, it produces relaxing factors including nitric oxide (NO), and participates in anti-contractile function[12].
A mean pulmonary artery pressure ≥ 25 mmHg constitutes PH. A number of disparate conditions are known to give rise to PH. PH is classified into 5 major clinical groups, that has recently been updated[13]. Group 1 labeled as pulmonary arterial hypertension (PAH) includes idiopathic, heritable PAH and PAH associated with bone morphogenic protein receptor II mutation, congenital heart defect, connective tissue diseases, portal hypertension, infection and drug toxicity. Included in this group are pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis as subcategory 1’, and recently, persistent pulmonary hypertension of the newborn was assigned the subcategory 1’’. The next 4 groups are labeled as PH; Group 2: PH associated with pulmonary venous hypertension secondary to left ventricular diseases, Group 3: chronic lung diseases and accompanying hypoxia leading to PH, Group 4: chronic thrombo-embolic PH and Group 5 includes miscellaneous diseases such as myeloproliferative diseases, thyroid, hematological and renal diseases. Irrespective of the underlying disease, the main features of PH are impaired vascular reactivity and remodeling, elevated pulmonary artery pressure and right ventricular hypertrophy, leading to right ventricular failure and premature death. Clinical and experimental studies suggest that the endothelial dysfunction/disruption may be an important underlying factor in the pathogenesis of PH. Importantly, endothelial dysfunction and molecular changes in pulmonary vasculature are reported to occur before the onset of PH[14,15].
Endothelial cells (EC) are heterogeneous; they play a specialized role in the context of a specific organ. EC modulate Ca2+ entry, produce vascular relaxants such as NO, prostacyclin and endothelium-derived hyperpolarizing factor and maintain vascular tone, and participate in barrier function. Inflammation plays an important role in the pathogenesis of PH. EC bear the major brunt of injuries such as increased pulmonary blood flow and shear stress, inflammation, chemical/drug toxicity, ventilation-induced injury and hypoxia resulting in endothelial dysfunction. In response to injury, EC become activated and secrete several cytokines and adhesion molecules that can affect coagulation, barrier function, and facilitate cellular adhesion and transmigration of leukocytes leading to EC dysfunction. Endothelial dysfunction leads to impaired vascular relaxation response, and the activation of proliferative and anti-apoptotic pathways, inflammatory response, and thrombogenic state leading to progressive vascular remodeling, elevated pressure and right ventricular hypertrophy[16].
In the 1950s, Palade and Yamada independently described caveolae, 50-100 nm flask shaped invaginations rich in cholesterol and sphingolipids. Caveolae are a subset of lipid rafts found on the plasmalemmal membranes of a variety of cells including endothelial, smooth muscle, epithelial cells, fibroblasts and adipocytes. Caveolae serve as a platform and compartmentalize the signaling molecules that reside in or are recruited to caveolae. Caveolae are also involved in transcytosis, endocytosis, potocytosis, and in the regulation of cell proliferation, differentiation and apoptosis via a number of diverse signaling pathways. Three isoforms of caveolin gene family have been identified. Caveolin-3 is muscle specific, found primarily in skeletal and cardiac myocytes. Caveolin-2 co-localizes with caveolin-1 and requires caveolin-1 for its membrane localization. Caveolin-1 (22 kD) is the major constitutive protein of caveolae[17]. Polymerase 1 and transcript receptor factor (PTRF/cavin), a caveolar coat protein, however, is required for caveolar formation and sequestration of caveolin-1 into caveolae[18]. Caveolin-1 is expressed in terminally differentiated cells including adipocytes, EC, epithelial cells, fibroblasts and myocytes. Caveolin-1 interacts and negatively regulates proteins such as Src family of kinases, G-proteins and G-protein-coupled receptors, eNOS, integrins and several growth factor receptors; and these interactions occur through caveolin-1-scaffolding domain (CSD, residue 82-101 in caveolin-1). For optimal activation, eNOS is targeted to caveolae, and caveolin-1 inhibits eNOS through its interaction. Heat shock protein (HSP) 90 binds to eNOS in a Ca2+-calmodulin-depedent manner, reducing the inhibitory influence of caveolin-1, and increasing eNOS activity. However, caveolin-1 is essential for proper eNOS activation. Caveolin-1 regulates Ca2+ entry into EC, which is important for eNOS activation as well as the activation of other vasodilators, prostacyclin and endothelium-derived hyperpolarizing factor[19]. In addition, caveolin-1 regulates not only eNOS-derived NO but also eNOS-derived superoxide. It is involved in the sequestration of uncoupled eNOS; it prevents eNOS oxidase activity, and inhibits superoxide formation[20]. Caveolin-1 keeps smooth muscle cells (SMC) in quiescence; and it modulates Ca2+ regulatory molecules, increases Ca2+ mobilization and facilitates contractile response to agonists. Disruption of caveolin-1 has been shown to reduce myogenic tone and impair contractile responses to several agonists[21,22]. The dynamic interrelationship between caveolin-1 and eNOS is critical for vascular homeostasis.
In several experimental models, the loss of endothelial caveolin-1 and the reciprocal activation of proliferative and antiapoptotic pathways such as PY-STAT3, cyclin D1 and Bcl-xL have been shown to occur before the onset of PH. The rescue of caveolin-1 inhibits the proliferative pathways and attenuates PH[15,23,24]. Besides, the mutation of caveolin-1 gene in humans is reported to be associated with PH[25]. Studies with caveolin-1 knockout mice have further highlighted the importance of caveolin-1 in pulmonary vasculature. The re-expression of endothelial caveolin-1 has been shown to attenuate PH, vascular dysfunction and cardiomyopathy in these mice[26]. Increased expression of PDGF-R β, the activation of PY-STAT3 and its downstream signaling pathways, cyclin D1 and Bcl-xL have been reported in pulmonary arteries from patients with PH as well as in the MCT and hypoxia models of PH[24,27-29]. The activation of PY-STAT3 is essential for PDGF-induced cell proliferation; and the inhibition of the PDGF receptor suppresses cell proliferation via the inactivation of STAT3 signaling[30,31]. Importantly, caveolin-1 acts as a suppressor of cytokine signaling, and inhibits PY- STAT3 activation and modulates proinflammatory cytokines[32] and it inhibits other proliferative pathways including PDGF-R β, cyclin D1, Bcl-xL. It promotes cell cycle arrest via a p53/p21waf1/cip1-dependent mechanism and regulates apoptosis by inhibiting survivin[33,34].
In the monocrotaline (MCT) model of PH, at 2 wk post-MCT, there is a significant loss of endothelial caveolin-1 associated with the activation of proliferative and anti-apoptotic pathways, PH and right ventricular hypertrophy. As the pulmonary vascular disease progresses, by 4 wk, extensive endothelial caveolin-1 loss and EC damage occur, followed by an enhanced expression of caveolin-1 in vascular SMC. This is associated with a significantly increased expression and the activity of matrix metalloproteinase (MMP) 2 that is known to participate in cell proliferation and cell migration. Normally, MMP2 is inhibited by caveolin-1; the activation of MMP2 in the presence of enhanced expression of caveolin-1 in SMC suggests that this caveolin-1 may have lost its inhibitory function[15]. Enhanced expression of caveolin-1 in SMC has been reported in patients with idiopathic PAH, PAH associated with congenital heart defect and drug-toxicity[35-37]. Pulmonary arterial SMC from idiopathic PAH revealed not only enhanced expression of caveolin-1, but also Ca2+ dysregulation and increased DNA synthesis which could be blocked by silencing caveolin-1[35]. This caveolin-1 in SMC becomes pro-proliferative, and facilitates cell proliferation and migration. The about face of caveolin-1 function in PH is not unlike what has been reported in cancer[17]. The effect of caveolin-1, thus, may depend on its location, conformation, state of the disease and cell context.
PPARγand pulmonary hypertension
PPARs constitute a subfamily of nuclear receptors, the master transcriptional regulators of nutrient metabolism and energy homeostasis. Three isoforms of PPAR have been identified (α, β/δ and γ). PPARα is thought to regulate fatty acid oxidation and glucose homeostasis, and is predominantly found in liver, muscle and kidneys. Recent studies have shown that PPAR β/δ agonists relax pulmonary and mesenteric arteries independent of cGMP and cAMP mechanisms. PPARγ is expressed in several types of tissue, including adipocytes, EC and SMC. It is an important regulator of genes involved in cell differentiation, cell growth, inflammation and angiogenesis. It forms an obligatory heterodimer with another nuclear receptor, retinoid-X-receptor which binds to peroxisome proliferator response elements that is located in the regulatory domains of genes[38,39]. PPARγ inhibits the production of chemokines in EC and the activation of NFκB[40]. In addition, it inhibits inter cellular adhesion molecules (ICAM) and vascular cellular adhesion molecules (VCAM)[41]. Furthermore, PPARγ increases NO production from EC and regulates superoxide generation at the EC membrane[42,43]. PPARγ has also been shown to reduce vascular SMC proliferation and migration[44]. In an arterial injury model, PPARγ was shown to have attenuated neointimal hyperplasia by modulating protein kinase G[45]. Reduction in the expression of PPARγ has been reported in human PAH and several experimental forms of PH such as vascular endothelial growth factor (VEGF) receptor blocker + hypoxia[46] and a shunt model[47] Endogenous ligand 15-deoxy-Δ(12,14) prostaglandin J2 and thiozolidinedione (TZD) compounds used in the treatment of diabetes activate PPARγ. Interestingly, TZD compound has been reported to attenuate the hypoxia-induced PH in mice[48]. However, PPARγ has also been shown to increase plasminogen activator inhibitor type-1 expression in EC which can affect vascular disease adversely[49]. PPARγ within the atheromatous lesion has a propensity to facilitate angiogenesis[50]. Furthermore, PPARγ not only upregulates caveolin-1 expression but also promotes some forms of cancer[51,52]. PPARγ does play an important role in vasculature but its effects may depend on the state of disease and the cellular context; and the activation of PPARγ may not be effective in all forms of PH.
Metabolic alterations that occur in PH negatively impact the disease. In PH, mitochondrial metabolic shift from oxidative phosphorylation to glycolytic pathway has been shown to occur in pulmonary vasculature as well as in the right ventricle. When this shift occurs in aerobic conditions, it is termed “Warburg effect” which leads to the down regulation of mitochondrial glucose oxidation. It is accompanied by fragmented, hyperpolarized mitochondrial reticulum, decreased superoxide dismutase2, metabolic shift, increased hypoxia inducible factor (HIF)-1α, and the activation of pyruvate dehydrogenase kinase[53]. Glycolytic pathway is associated with resistance to apoptosis; an important feature of PH. EC isolated from idiopathic PAH pulmonary arteries exhibit increased glycolytic rate, decreased mitochondrial DNA levels and fewer mitochondrial numbers per cell. In addition, increased glycolytic rate has also been shown to occur in the lungs of patients with idiopathic PAH[54]. Hyperpolarization of the mitochondrial membrane is thought to be a feature of Warburg phenotype, and apoptosis is induced by the activation of voltage-gated K+ channel (Kv) and depolarization of mitochondrial membrane[55]. Mitochondrial hyperpolarization is thought to be the underlying cause of the metabolic switch observed in PH. Importantly, the loss of caveolin-1 has been shown to lead to mitochondrial dysfunction, membrane hyperpolarization, and the mitochondrial production of oxidant species. Interestingly, the glycolysis inhibition abolishes the increase in oxidant species in caveolin-1 knock-down vascular EC[56], indicating that caveolin-1 may have a key role in the regulation of oxidative stress and metabolic switch. Recent studies have shown decreased expression of mitochondrial uncoupling protein2 and increased mitochondrial potential in pulmonary arterial SMC from patients with idiopathic PAH and from experimental models of PH. Interestingly, reactive oxygen species inhibitors decrease cell proliferation in pulmonary arterial SMC with absent mitochondrial uncoupling protein2 expression[57]. In addition, treatment with dichloroacetate that increases the mitochondrial oxidative phosphorylation has been shown not only to prevent but also to reverse MCT-induced PH[58]. Thus, controlling metabolic dysfunction in PH may be a valuable therapeutic measure to prevent the progression of the disease or possibly to reverse it.
Adipose tissue produces a number of bioactive substances including leptin, adeponetin, and inflammatory cytokines such as interleukin (IL)-6, tumor necrosis factor (TNF)-α and visfatin, and proteins such as apolipoprotein E (ApoE), plasminogen activator inhibitor 1 and apelin[59,60]. These substances influence adipose tissue and vasculature in health and disease.
PVAT surrounds blood vessels to provide support and to maintain vascular homeostasis. Close anatomical relationship between PVAT and blood vessels allows crosstalk which is essential for both vascular and metabolic homeostasis. Anti-contractile activity of PVAT is thought to be due to the release of adipose-derived relaxing factor[61]. In addition to the adipose-derived relaxing factor, PVAT releases other vaso-active factors including adiponectin, leptin, angiotensin (1-7) and NO. Under normal conditions these factors maintain vascular function and resistance[12]. PVAT shares common features with brown fat tissue, which is important for thermogenesis and plays a protective role[62].
Adiponectin was initially recognized as an insulin-sensitizing factor, now it has been found to have a role in vascular homeostasis and inflammation. Adiponectin is an anti-inflammatory adipokine; its levels are reduced in obesity. Adiponectin plays a central role in the development of metabolic syndrome and atherosclerosis; both have a low grade inflammation. Adiponectin knockout mice show an exaggerated inflammatory response and produce increased lipopolysaccharides-induced expression of VCAM-1 and ICAM-1. Treatment with adiponectin results in a dose-dependent inhibition of TNF-α-induced monocytes adhesion to EC and the expression of VCAM-1[63]. Interestingly, adiponectin is present in vascular EC at steady state, and it has been shown to have a significant role in vascular relaxation by activating eNOS[64], and PGI2 synthase[65]. High molecular weight adiponectin stimulates eNOS phosphorylation accompanied by eNOS-HSP90-Akt complex formation and increases NO production in a dose-dependent manner; and it also inhibits caspase3 activity and promotes endothelial survival[66,67].
Adiponectin produced in perivascular tissue is highly regulated by PPARγ. Furthermore, PVAT regulates insulin-mediated vasorelaxation in adiponectin-dependent pathway. It increases eNOS activation as well as inhibits superoxide generation. Local expression of adiponectin gene and protein is increased in the presence of oxidative stress. Under oxidative stress and in the presence of low tetrahydrobiopterin, eNOS is uncoupled and generates superoxide. Under these circumstances adiponectin may increase superoxide generation by increasing eNOS activation[68,69].
Removal of PVAT has been shown to enhance neointima formation; and the local but not the systemic administration of adiponectin reduces neointima formation[70]. Obesity-induced inflammation causes increased production of pro-inflammatory adipokines and reduction in anti-inflammatory adiponectin, which contribute to pathological vascular remodeling in response to injury. Deletion of adeponectin in mice leads to PH, perivascular inflammatory infiltrates and the upregulation of E selectin[71]. Recent studies have shown increased plasma levels of adiponectin associated with endothelial dysfunction in diabetic nephropathy[72]. This suggests that the adiponectin levels increase in response to endothelial dysfunction and that the endothelial integrity may be necessary for normal adiponectin function.
Leptin, primarily expressed by adipocytes is involved in energy expenditure and plays a key role in inhibiting food intake and improving insulin sensitivity. In obese patients, the circulating leptin levels are high but they exhibit resistance to the effects of leptin. Congenital leptin deficiency is associated with marked obesity and hypogonadism[73]. Increased risk of cardiovascular diseases has been reported in obese patients with elevated levels of leptin. Leptin is considered a link between metabolic disorders and immune responses. Usually, leptin increases during the course of acute infection and inflammation. Leptin has been shown to have a direct effect on T lymphocyte type 1 helper response, and leptin alters T regulatory (Treg) response. Defective leptin receptor signaling in Treg cells reduces the development of atherosclerosis[74]. Leptin negatively affects the generation and the proliferation of the Treg cells[75], and it promotes chronic autoimmune disorders by regulating Treg cells and their function[76].
Leptin receptors are expressed in EC, SMC and macrophages. Leptin induces vasoconstriction via the stimulation of sympathetic activity; and depending on intact and functional EC, it has a direct vasodilatory effect via NO release. In systemic hypertensive rats, a reduction in leptin levels is accompanied by a loss of perivascular anti-contractile function secondary to the impaired activation of eNOS[77]. In contrast, obesity-induced increased expression of leptin enhances neointima formation. Even in the absence of obesity and increased circulating levels of leptin, overexpression of leptin in PVAT facilitates neointima formation[78]. In cell culture studies, leptin has been shown to induce vascular SMC proliferation and migration[79]. Furthermore, pulmonary arterial EC from patients with PAH, and PAH associated with scleroderma secrete leptin. In addition, Treg cells from these patients exhibit increased expression of leptin receptor (ObR) on the membrane[80], indicating that leptin may have a significant role in the pathogenesis and progression of PH.
ApoE is primarily produced in liver, but other cells such as adipocytes and macrophages also produce it, but not the preadipocytes[60]. Circulating ApoE plays an important role in the metabolism of lipoproteins. Adipocytes from ApoE knockout mice are smaller. Systemic deficiency of ApoE results in impaired clearance of triglycerides and resistance to obesity[81]. Diet-induced or leptin-deficient obesity produces a significant reduction in ApoE expression in adipocytes. Inflammatory cytokines such as TNF-α and reactive oxygen species suppress ApoE expression, whereas systemic administration of PPARγ increases ApoE expression. Interestingly, ApoE colocalizes with caveolin-1 in adipocytes, and the loss of ApoE results in the alterations in caveolar lipid composition and a significant reduction in caveolin-1 mRNA expression. Endogenous expression of ApoE preserves caveolar composition in adipocytes[82,83]. ApoE is not produced in EC, but macrophage-related ApoE is internalized by EC. ApoE increases the endothelial NO production by modulating caveolin-1/eNOS interaction and it suppresses endothelial activation, and inhibits VCAM-1 expression via eNOS stimulation and NO production. Interestingly, ApoE has been shown to co-precipitate with caveolin-1 but not with eNOS. Deficiency of ApoE is associated with hypercholesterolemia, and the loss of its effect on eNOS activation leads to endothelial dysfunction[84,85]. Ablation of caveolin-1 in ApoE knockout mice has shown to be protective against atherosclerosis[86]. However, PPARγ-induced increase in caveolin-1 expression in ApoE knockout mice confers protection against atherosclerosis[87]. The opposing effects of caveolin-1 may be dependent on its location and conformation. Interestingly, male ApoE knockout mice on high fat diet and associated insulin resistance have been shown to develop PH, which can be reversed by PPARγ activation[88].
Other bioactive substances produced by adipose tissue are visfatin and apelin. Visfatin has been shown to stimulate SMC growth and angiogenesis. Apelin causes NO-dependent vascular relaxation, but it is a potent vascoconstrictor in endothelium-denuded vessels[59]. The foregoing observations indicate that adipose tissue, especially PVAT possesses direct vascular protective effects which are reduced or lost in obesity, resulting in an increased incidence of vascular diseases. Even in the absence of obesity, but in the presence of alterations in the balance of bioactive substances produced by PVAT can significantly influence the state of the vasculature.
Adipose tissue has a critical role in energy balance and insulin sensitivity. A complex network of transcripton factors is involved in adipogenesis. White adipose tissue is the predominant type in adults and it functions as a storage depot for energy; whereas the brown adipose tissue generates heat through mitochondrial uncoupling of lipid peroxidation. Adipose tissue consists of adipocytes, preadipocytes, leukocytes, macrophages and EC. Adipocytes are an active metabolic organ that secretes a number of adipokines including leptin, adiponectin and resistin, and are involved in glucose and lipid metabolism, energy homeostasis; and it modulates inflammation and vascular reactivity. In addition, adipose tissue secretes proinflammatory cytokines such as IL-6, IL-1, TNF-α and CC-chemokine ligand 2[89-92].
Inflammation plays a significant role in metabolic syndrome, and the adipocytes are considered the primary site of inflammation. Metabolic syndrome includes a number of alterations such as increased waist circumference, systemic hypertension, increased levels of glucose, and impaired cholesterol and triglyceride metabolism. The major categories included in the metabolic syndrome are obesity, disorders of adipose tissue and insulin resistance. There is a positive correlation between cardiovascular diseases and the components of metabolic syndrome such as abdominal obesity, atherogenic dyslipidemia, insulin resistance with or without glucose intolerance, and the presence of pro-inflammatory and pro-thrombogenic factors[93].
Recent studies show that EC play a key role in metabolic homeostasis. VEGF-B interacts with endothelial VEGF receptor1 also known as FLT1, and regulates endothelial transport of fatty acids into cardiac and skeletal muscle. Over expression of VEGF-B can lead to mitochondrial dysfunction, altered cardiac lipid metabolism and hypertrophy, and insulin resistance. Mice lacking VEGF-B have been shown to display decreased fatty acid uptake and lipid deposition in muscle cells. Furthermore, VEGF-B inhibition improves insulin sensitivity[94-96]. In addition to VEGF-B, PPARγ and apelin also have a role in fatty acid uptake by EC and coordinate it with the energy demand and to accommodate energy needs during fasting[97].
Caveolin-1 in adipocytes plays an important role in glucose and lipid metabolism. Insulin receptor (IR) colocalizes with caveolin-1, and caveolin-1 stabilizes IR-β subunit at the cell membrane. It stimulates IR signaling and linking insulin action to glucose uptake. Insulin recruits glucose transporter (GLUT) 4 for glucose uptake and caveolin-1 is required for its internalization after insulin removal[98-101]. Thus, caveolin-1 plays an important role in the control of insulin signaling and facilitates GLUT4-mediated glucose uptake.
Leptin has been shown to increase the expression of caveolin-1 in adipocytes and EC, and in contrast, caveolin-1 impairs leptin signaling which in part may be responsible for inducing leptin resistance and endothelial dysfunction[102,103]. Interestingly, patients with obesity and obesity-associated type 2 diabetes, exhibit increased expression of caveolin-1 mRNA. This increase in caveolin-1 mRNA is associated with an increased expression of inflammatory markers such as leptin, C-reactive protein, MCP-1 and TNF-α[104]. In diabetic mice, increased expression of caveolin-1 mRNA and protein has been shown to be associated with impaired endothelium-dependent relaxation response despite normal eNOS expression[105]. It is likely that caveolin-1 forms a tight complex with eNOS inhibiting its activation, not unlike what is seen in the hypoxia-induced PH. In the hypoxia model of PH, the disruption of cholesterol results in the separation of caveolin-1 and eNOS resulting in increased NO production[106].
Caveolae are also the site of fatty acid entry. The enzymes involved in de novo synthesis of triacylglycerol from fatty acids, and glycerol-3 phosphatase are localized in the subclass of caveolae in the plasma membrane of primary adipocytes[107]. Caveolin-1 regulates triglycerides, lipoprotein metabolism and cholesterol homeostasis, and participates in lipid storage via transcytosis and also in its breakdown. In addition, it targets the lipid droplet accumulation in the cells. In atherosclerosis, caveolin-1 has been shown to promote cholesterol accumulation via transcytosis across EC, thus, negatively impacting the disease. Loss of caveolin-1 leads to decreased lipid accumulation resulting in progressive white adipose tissue atrophy[108-110]. Recent studies have shown caveolin-1 gene mutations to be associated with the atypical and severe forms of lipodystrophy and hypertriglyceridemia[111,112]. Furthermore, mutation of PTRF associated with a reduction in caveolin has been reported in patients with generalized lipodystrophy and muscular dystrophy[113]. Loss of caveolin-1 causes significant metabolic alterations, increased glucose production in the liver and metabolic inflexibility. Metabolic flexibility is the function of adjusting the changing nutrient availability. Adiponectin has been thought to provide the metabolic flexibility. Interestingly, caveolin-1 knockout mice exhibit low circulating adiponectin despite increased mRNA and intracellular adiponectin[114].
Studies with caveolin-1 knockout mice have revealed the importance of caveolin-1 in maintaining vascular and metabolic homeostasis. Caveolin-1 knockout mice exhibit PH and cellular hyperplasia in the lungs, cardiomyopathy, and metabolic deregulation. These mice are found to be resistant to diet-induced obesity, but have hypertriglycedemia and develop insulin resistance on normal diet[98]. In addition, they exhibit increased macrophage infiltration, increased capacity for IL-6 production and an increased collagen deposition leading to increased fibrosis. Adipose tissue from these mice show increased lipolysis[115]. Re-expression of endothelial-specific caveolin-1 ameliorates cardiopulmonary changes, but has no effect on the lack of caveolin-1 in adipocytes that accounts for lipoatrophy. The endothelial-specific caveolin-1 expression, however, limits the macrophage extravasations into adipose tissue[116], indicating a significant role of endothelial caveolin-1 in modulating adipocytes-driven inflammatory response.
PPARγand metabolic syndrome
Adipose tissue especially the white adipose tissue is the major site for PPARγ expression. PPARγ is required for adipocytes differentiation. Activation of PPARγ in fibroblastic cells leads to cell differentiation and lipid accumulation; and in addition, these cells acquire genes characteristic of fat cells[117]. PPARγ is expressed to a lesser degree in insulin target tissues such as liver and skeletal muscle. Muscle-specific PPARγ is critical for maintaining the whole body response to insulin. The loss of muscle-specific PPARγ leads to obesity and insulin resistance[118]. In addition, targeted EC deletion of PPARγ plays an important role in insulin resistance and hyperlipedemia-mediated hypertension[119].
Impaired PPARγ function is implicated in a number of metabolic disorders such as type2 diabetes, obesity and lipodystrophy. In humans, mutation of PPARγ leads to obesity and severe insulin resistance. Overexpression of this mutant gene in murine fibroblasts leads to accelerated differentiation into adipocytes and increased cellular accumulation of triglycerides[120]. PPARγ mutation is reported to be associated with insulin resistance, diabetes and hypertension[121], and also in cases of lipodystrophy associated with activated renin-angiotensin system and ensuing oxidative stress and hypertension[122]. Defect in PPARγ expression plays a significant role in PH as well as in the pathogenesis of fibrosis; importantly, scleroderma exhibits both these features[123]. The anti-fibrotic activity of PPARγ is thought to be mediated by hepatocyte growth factor and adiponectin. Adiponectin, an anti-inflammatory adipokine and a fat-specific target of PPARγ prevents hepatic fibrosis in mice[124] and hypoxia-induced PH[125]. The administration of leptin, a proinflammatory adipokine has been found to reduce the expression and activity of PPARγ in human lung fibroblasts and to augment TGF β-mediated fibro-proliferative response. Furthermore, the loss of leptin prevents bleomycin-induced lung fibrosis in mice[126].
PPARγ inhibits the production of adipokine/cytokines such as resistin, IL-6 and TNF-α, all known to promote insulin resistance. PPARγ agonist-induced adiponectin levels are reported to be low in type 2 diabetes[127]. Adiponectin increases fatty acid oxidation in liver and skeletal muscle, resulting in improved insulin sensitivity in skeletal muscle, and decreased glucose production in the liver, thus, leading to the reduction in circulating glucose, free fatty acid and triglycerides[128]. These results suggest a protective role of PPARγ, and the crosstalk between PPARγ and adipokines determines the progression of a given metabolic/vascular disease process. PPARγ activators, TZD group of drugs have been used clinically to treat type 2 diabetes. TZDs increase the expression of proteins required for insulin signaling, and also reduce the circulating levels of low density lipoproteins and triglycerides. Furthermore, they attenuate the production of inflammatory mediators[129,130]. However, TZDs are also reported to have side effects such as increased fluid retention, increased risk of congestive heart failure, decrease in bone mineral density and fractures. Selective PPARγ modulator in experimental studies has been shown not only to increase insulin sensitivity but also to improve bone density[131,132]. Selective PPARγ modulation, thus, may significantly reduce the side effects of TZD.
Obesity is reported to be associated with PH, but the prevalence of PH in obesity is not known. The echocardiographic studies in 3790 normal subjects revealed higher pulmonary artery pressure to correlate with age, body mass index and gender; the incidence being higher in males[133]. Importantly, higher frequency of obesity, diabetes and hyperlipidemia was found in patients with precapillary PH[134]. Furthermore, obesity is a risk factor in patients with elevated pulmonary venous pressure and preserved left ventricular ejection fraction[135].
Diabetes is reported to be associated with PH independent of coronary artery disease and congestive heart failure[136], and insulin resistance is more prevalent in female patients[137]. Recent REVEAL registry analysis showed a high incidence of obesity (M:F, 31%:34%) among patients with PAH; and associated comorbidities such as diabetes and chronic obstructive pulmonary disease had a negative impact on prognosis[138,139]. In experimental studies, diabetes associated with moderate hypoxia is reported to exhibit significant endothelial dysfunction, elevated pulmonary artery pressure and RVH. It was diabetes and not the moderate hypoxia that was found to be responsible for endothelial dysfunction[140]. These observations suggest that obesity and insulin resistance negatively impact PH.
HIF-1α, an O2 sensor is a subunit of a family of HIF transcription factors. HIF-1α regulates numerous genes involved in adaptive responses to hypoxia and modulates metabolism, growth and angiogenesis; and promotes adaptation and cell survival under hypoxic condition. VEGF, critical for angiogenesis, is one of the target genes of HIF-1α[141]. Under normoxic conditions HIF-1α is degraded. Evidence is accumulating to suggest that reactive oxygen species (ROS) generated by mitochondrial complex III is required for HIF-1α activation and stabilization; and in turn HIF-1α activation prevents increased production of ROS in hypoxic cells[142]. Under hypoxic conditions, cells depend on glycolysis for ATP production; and HIF-1α is necessary for metabolic switch during hypoxia[143]. Destabilization of HIF-1α has a negative impact on cell and tissue adaptation to hypoxia.
HIF-1α has been implicated in the pathogenesis of PH. HIF-1α plays a role in cell proliferation, angiogenesis, and participates in vascular remodeling. In plexiform lesions, the proliferating EC have been shown to express HIF-1α, its target gene VEGF and VEGF receptor 2[144]. Recent studies have shown that the deletion of HIF-1α in SMC attenuates hypoxia-induced PH and vascular remodeling[145]. In some types of cancer cells, HIF-1α under hypoxia conditions upregulates caveolin-1 and promotes ligand-independent activation of epidermal growth factor receptor, and increases cell proliferation and cell migration[146]. Interestingly, HIF-1α has also been shown to maintain pulmonary vascular tone during hypoxia and normoxia by decreasing myosin light chain phosphorylation; and the lack of HIF-1α increases pulmonary vascular tone[147]. In addition, the loss of HIF-1α in SMC from systemic vessels causes systemic hypertension and an exaggerated response to angiotensin II. HIF-1α is reported to decrease the expression of angiotensin II receptor type 1. Importantly, the HIF-1α-induced decrease in the expression of angiotensin II receptor type 1 is mediated by PPARγ[148]. In addition, HIF-1α has been shown to play a protective role in the adaptation of the heart and aorta to pressure overload by regulating TGF-β signaling in EC[149].
HIF-1α is an important regulator of glucose transport by altering GLUT1 expression in EC. Absence of HIF-1α is associated with significant defect in glucose uptake. Reduced glucose uptake in HIF-1α-deficient EC can be rescued by increased expression of GLUT1 DNA, underscoring the critical the role played by HIF-1α in glucose metabolism[150], and that the vascular dysfunction may contribute to abnormal glucose handling. Hyperglycemia has been shown to impair hypoxia-dependent stabilization of HIF-1α[151]. Both hyperglycemia and hypoxia are known to occur in diabetes. Hyperglycemia-induced destabilization of HIF-1α negatively affects the tissue adaptation to hypoxia, resulting in complications such as diabetic retinopathy, cardiovascular and renal diseases[152]. In addition, deficiency of HIF-1α has been shown to block stromal derived factor1 and impair mobilization of bone marrow-derived angiogenic cells, thus adversely affecting wound healing[153]. Interestingly, hypoxia has been shown to cause insulin resistance and the inhibition of HIF-1α in adipose tissue improves insulin resistance[154]. Thus, both in PH and metabolic syndrome, the role of HIF-1α may depend on the cells, disease state and the interaction of HIF-1α with other factors including caveolin-1 and PPARγ.
Caveolin-1 and PPARγ are abundantly expressed in EC and adipocytes. Under normal conditions, caveolin-1 and PPARγ interact with adipokines (pro- and anti-inflammatory) and form a complex network to maintain metabolic and vascular homeostasis. Genetic mutations of caveolin-1 and PPARγ lead to vascular and metabolic diseases. PVAT has a direct role in maintaining vascular reactivity. Disruption of PVAT results in the loss of anti-inflammatory and anti-contractile factors leading to endothelial dysfunction. The initial loss of endothelial caveolin-1 results in the activation of proliferative pathways leading to vascular remodeling and PH. As the disease progresses, SMC develop enhanced expression of caveolin-1. This caveolin-1 becomes pro-proliferative and participates in cell proliferation and cell migration. In adipose tissue, the loss of caveolin-1 is associated with dysregulation of insulin and lipid metabolism. However, increased levels of caveolin-1 in diabetes and hypercholesterolemia result in eNOS dysfunction. Loss of PPARγ leads to vascular and metabolic diseases. Interestingly, PPARγ within the atheromatous lesion facilitates angiogenesis. Adiponectin, regulated by PPARγ increases insulin sensitivity, inhibits inflammation and facilitates NO production, thus, plays an important role in maintaining vascular and metabolic homeostasis. Leptin, a proinflammatory adipokine has an important role in food intake and energy conservation. Under normal conditions, leptin has a vasodilatory effect. However, obesity-induced increased levels of leptin cause endothelial dysfunction. It increases caveolin-1 expression which in turns inhibits leptin.
Vasculature and adipose tissue owing to their proximity share the complex network of transcription factors, and influence each other in health and disease. The network of these factors is rather complex and delicate, which can be deregulated by injury and/or inflammatory process leading to a stage where the cytoprotective factors become cytotoxic depending on the state of the cell/organ. Rudolf Virchow (1821-1902) a German physician is reported to have said “The body is a Cell State in which every cell is a citizen. Disease is merely the conflict of citizens of the State brought about by the action of an external force”. It is not difficult to imagine that this conflict can easily spill into the neighboring organs/systems.
P- Reviewer: Trimarchi H S- Editor: Wen LL L- Editor: A E- Editor: Wu HL
| 1. | Fuentes E, Fuentes F, Vilahur G, Badimon L, Palomo I. Mechanisms of chronic state of inflammation as mediators that link obese adipose tissue and metabolic syndrome. Mediators Inflamm. 2013;2013:136584. [PubMed] [DOI] [Cited in This Article: ] [Cited by in F6Publishing: 1] [Reference Citation Analysis (0)] |
| 2. | Hotamisligil GS, Shargill NS, Spiegelman BM. Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science. 1993;259:87-91. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 5334] [Cited by in F6Publishing: 5219] [Article Influence: 168.4] [Reference Citation Analysis (0)] |
| 3. | Bhargava A, Kumar A, Yuan N, Gewitz MH, Mathew R. Monocrotaline induces interleukin-6 mRNA expression in rat lungs. Heart Dis. 1999;1:126-132. [PubMed] [Cited in This Article: ] |
| 4. | Humbert M, Monti G, Brenot F, Sitbon O, Portier A, Grangeot-Keros L, Duroux P, Galanaud P, Simonneau G, Emilie D. Increased interleukin-1 and interleukin-6 serum concentrations in severe primary pulmonary hypertension. Am J Respir Crit Care Med. 1995;151:1628-1631. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 553] [Cited by in F6Publishing: 544] [Article Influence: 18.8] [Reference Citation Analysis (0)] |
| 5. | Tuder RM, Groves B, Badesch DB, Voelkel NF. Exuberant endothelial cell growth and elements of inflammation are present in plexiform lesions of pulmonary hypertension. Am J Pathol. 1994;144:275-285. [PubMed] [Cited in This Article: ] |
| 6. | Perros F, Dorfmüller P, Montani D, Hammad H, Waelput W, Girerd B, Raymond N, Mercier O, Mussot S, Cohen-Kaminsky S. Pulmonary lymphoid neogenesis in idiopathic pulmonary arterial hypertension. Am J Respir Crit Care Med. 2012;185:311-321. [PubMed] [DOI] [Cited in This Article: ] [Cited by in F6Publishing: 1] [Reference Citation Analysis (0)] |
| 7. | Burke DL, Frid MG, Kunrath CL, Karoor V, Anwar A, Wagner BD, Strassheim D, Stenmark KR. Sustained hypoxia promotes the development of a pulmonary artery-specific chronic inflammatory microenvironment. Am J Physiol Lung Cell Mol Physiol. 2009;297:L238-L250. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 108] [Cited by in F6Publishing: 115] [Article Influence: 7.7] [Reference Citation Analysis (0)] |
| 8. | Razani B, Combs TP, Wang XB, Frank PG, Park DS, Russell RG, Li M, Tang B, Jelicks LA, Scherer PE. Caveolin-1-deficient mice are lean, resistant to diet-induced obesity, and show hypertriglyceridemia with adipocyte abnormalities. J Biol Chem. 2002;277:8635-8647. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 434] [Cited by in F6Publishing: 435] [Article Influence: 19.8] [Reference Citation Analysis (0)] |
| 9. | Sowa G. Caveolae, caveolins, cavins, and endothelial cell function: new insights. Front Physiol. 2012;2:120. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 134] [Cited by in F6Publishing: 126] [Article Influence: 10.5] [Reference Citation Analysis (0)] |
| 10. | Duan SZ, Usher MG, Mortensen RM. Peroxisome proliferator-activated receptor-gamma-mediated effects in the vasculature. Circ Res. 2008;102:283-294. [PubMed] [DOI] [Cited in This Article: ] [Cited by in F6Publishing: 45] [Reference Citation Analysis (0)] |
| 11. | Rosen ED, Spiegelman BM. PPARgamma : a nuclear regulator of metabolism, differentiation, and cell growth. J Biol Chem. 2001;276:37731-37734. [PubMed] [Cited in This Article: ] |
| 12. | Fernández-Alfonso MS, Gil-Ortega M, García-Prieto CF, Aranguez I, Ruiz-Gayo M, Somoza B. Mechanisms of perivascular adipose tissue dysfunction in obesity. Int J Endocrinol. 2013;2013:402053. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 64] [Cited by in F6Publishing: 64] [Article Influence: 5.8] [Reference Citation Analysis (0)] |
| 13. | Simonneau G, Gatzoulis MA, Adatia I, Celermajer D, Denton C, Ghofrani A, Gomez Sanchez MA, Krishna Kumar R, Landzberg M, Machado RF. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2013;62:D34-D41. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 1912] [Cited by in F6Publishing: 2067] [Article Influence: 187.9] [Reference Citation Analysis (0)] |
| 14. | Mathew R, Huang J, Shah M, Patel K, Gewitz M, Sehgal PB. Disruption of endothelial-cell caveolin-1alpha/raft scaffolding during development of monocrotaline-induced pulmonary hypertension. Circulation. 2004;110:1499-1506. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 108] [Cited by in F6Publishing: 118] [Article Influence: 5.9] [Reference Citation Analysis (0)] |
| 15. | Huang J, Wolk JH, Gewitz MH, Mathew R. Caveolin-1 expression during the progression of pulmonary hypertension. Exp Biol Med (Maywood). 2012;237:956-965. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 24] [Cited by in F6Publishing: 28] [Article Influence: 2.3] [Reference Citation Analysis (0)] |
| 16. | Mathew R. Pulmonary hypertension: endothelial cell function in Pulmonary hypertension: from bench research to clinical challenges (pp 1-24). Sulica R and Preston I. Eds. Croatia: Intech 2011; 1-24. [Cited in This Article: ] |
| 17. | Mathew R. Cell-specific dual role of caveolin-1 in pulmonary hypertension. Pulm Med. 2011;2011:573432. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 31] [Cited by in F6Publishing: 36] [Article Influence: 2.8] [Reference Citation Analysis (0)] |
| 18. | Hill MM, Bastiani M, Luetterforst R, Kirkham M, Kirkham A, Nixon SJ, Walser P, Abankwa D, Oorschot VM, Martin S. PTRF-Cavin, a conserved cytoplasmic protein required for caveola formation and function. Cell. 2008;132:113-124. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 538] [Cited by in F6Publishing: 548] [Article Influence: 34.3] [Reference Citation Analysis (0)] |
| 19. | Mathew R. Pathogenesis of pulmonary hypertension: a case for caveolin-1 and cell membrane integrity. Am J Physiol Heart Circ Physiol. 2014;306:H15-H25. [PubMed] [DOI] [Cited in This Article: ] [Cited by in F6Publishing: 1] [Reference Citation Analysis (0)] |
| 20. | Karuppiah K, Druhan LJ, Chen CA, Smith T, Zweier JL, Sessa WC, Cardounel AJ. Suppression of eNOS-derived superoxide by caveolin-1: a biopterin-dependent mechanism. Am J Physiol Heart Circ Physiol. 2011;301:H903-H911. [PubMed] [DOI] [Cited in This Article: ] [Cited by in F6Publishing: 8] [Reference Citation Analysis (0)] |
| 21. | Adebiyi A, Narayanan D, Jaggar JH. Caveolin-1 assembles type 1 inositol 1,4,5-trisphosphate receptors and canonical transient receptor potential 3 channels into a functional signaling complex in arterial smooth muscle cells. J Biol Chem. 2011;286:4341-4348. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 65] [Cited by in F6Publishing: 67] [Article Influence: 4.8] [Reference Citation Analysis (0)] |
| 22. | Dreja K, Voldstedlund M, Vinten J, Tranum-Jensen J, Hellstrand P, Swärd K. Cholesterol depletion disrupts caveolae and differentially impairs agonist-induced arterial contraction. Arterioscler Thromb Vasc Biol. 2002;22:1267-1272. [PubMed] [DOI] [Cited in This Article: ] [Cited by in F6Publishing: 1] [Reference Citation Analysis (0)] |
| 23. | Huang J, Kaminski PM, Edwards JG, Yeh A, Wolin MS, Frishman WH, Gewitz MH, Mathew R. Pyrrolidine dithiocarbamate restores endothelial cell membrane integrity and attenuates monocrotaline-induced pulmonary artery hypertension. Am J Physiol Lung Cell Mol Physiol. 2008;294:L1250-L1259. [PubMed] [DOI] [Cited in This Article: ] [Cited by in F6Publishing: 9] [Reference Citation Analysis (0)] |
| 24. | Jasmin JF, Mercier I, Dupuis J, Tanowitz HB, Lisanti MP. Short-term administration of a cell-permeable caveolin-1 peptide prevents the development of monocrotaline-induced pulmonary hypertension and right ventricular hypertrophy. Circulation. 2006;114:912-920. [PubMed] [DOI] [Cited in This Article: ] [Cited by in F6Publishing: 4] [Reference Citation Analysis (0)] |
| 25. | Austin ED, Ma L, LeDuc C, Berman Rosenzweig E, Borczuk A, Phillips JA, Palomero T, Sumazin P, Kim HR, Talati MH. Whole exome sequencing to identify a novel gene (caveolin-1) associated with human pulmonary arterial hypertension. Circ Cardiovasc Genet. 2012;5:336-343. [PubMed] [DOI] [Cited in This Article: ] [Cited by in F6Publishing: 3] [Reference Citation Analysis (0)] |
| 26. | Murata T, Lin MI, Huang Y, Yu J, Bauer PM, Giordano FJ, Sessa WC. Reexpression of caveolin-1 in endothelium rescues the vascular, cardiac, and pulmonary defects in global caveolin-1 knockout mice. J Exp Med. 2007;204:2373-2382. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 188] [Cited by in F6Publishing: 201] [Article Influence: 11.8] [Reference Citation Analysis (0)] |
| 27. | Perros F, Montani D, Dorfmüller P, Durand-Gasselin I, Tcherakian C, Le Pavec J, Mazmanian M, Fadel E, Mussot S, Mercier O. Platelet-derived growth factor expression and function in idiopathic pulmonary arterial hypertension. Am J Respir Crit Care Med. 2008;178:81-88. [PubMed] [DOI] [Cited in This Article: ] [Cited by in F6Publishing: 1] [Reference Citation Analysis (0)] |
| 28. | Schermuly RT, Dony E, Ghofrani HA, Pullamsetti S, Savai R, Roth M, Sydykov A, Lai YJ, Weissmann N, Seeger W. Reversal of experimental pulmonary hypertension by PDGF inhibition. J Clin Invest. 2005;115:2811-2821. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 780] [Cited by in F6Publishing: 746] [Article Influence: 39.3] [Reference Citation Analysis (0)] |
| 29. | Huang J, Wolk JH, Gewitz MH, Mathew R. Progressive endothelial cell damage in an inflammatory model of pulmonary hypertension. Exp Lung Res. 2010;36:57-66. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 37] [Cited by in F6Publishing: 41] [Article Influence: 2.9] [Reference Citation Analysis (0)] |
| 30. | Hirai T, Masaki T, Kuratsune M, Yorioka N, Kohno N. PDGF receptor tyrosine kinase inhibitor suppresses mesangial cell proliferation involving STAT3 activation. Clin Exp Immunol. 2006;144:353-361. [PubMed] [Cited in This Article: ] |
| 31. | Mathew R. PDGF receptor blocker for pulmonary hypertension: a new agent in therapeutic arsenal. Expert Opin Investig Drugs. 2012;21:139-142. [PubMed] [DOI] [Cited in This Article: ] [Cited by in F6Publishing: 3] [Reference Citation Analysis (0)] |
| 32. | Jasmin JF, Mercier I, Sotgia F, Lisanti MP. SOCS proteins and caveolin-1 as negative regulators of endocrine signaling. Trends Endocrinol Metab. 2006;17:150-158. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 34] [Cited by in F6Publishing: 42] [Article Influence: 2.3] [Reference Citation Analysis (0)] |
| 33. | Galbiati F, Volonté D, Liu J, Capozza F, Frank PG, Zhu L, Pestell RG, Lisanti MP. Caveolin-1 expression negatively regulates cell cycle progression by inducing G(0)/G(1) arrest via a p53/p21(WAF1/Cip1)-dependent mechanism. Mol Biol Cell. 2001;12:2229-2244. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 226] [Cited by in F6Publishing: 227] [Article Influence: 9.9] [Reference Citation Analysis (0)] |
| 34. | Torres VA, Tapia JC, Rodríguez DA, Párraga M, Lisboa P, Montoya M, Leyton L, Quest AF. Caveolin-1 controls cell proliferation and cell death by suppressing expression of the inhibitor of apoptosis protein survivin. J Cell Sci. 2006;119:1812-1823. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 88] [Cited by in F6Publishing: 94] [Article Influence: 5.2] [Reference Citation Analysis (0)] |
| 35. | Patel HH, Zhang S, Murray F, Suda RY, Head BP, Yokoyama U, Swaney JS, Niesman IR, Schermuly RT, Pullamsetti SS. Increased smooth muscle cell expression of caveolin-1 and caveolae contribute to the pathophysiology of idiopathic pulmonary arterial hypertension. FASEB J. 2007;21:2970-2979. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 98] [Cited by in F6Publishing: 104] [Article Influence: 6.1] [Reference Citation Analysis (0)] |
| 36. | Mathew R, Huang J, Katta US, Krishnan U, Sandoval C, Gewitz MH. Immunosuppressant-induced endothelial damage and pulmonary arterial hypertension. J Pediatr Hematol Oncol. 2011;33:55-58. [PubMed] [DOI] [Cited in This Article: ] [Cited by in F6Publishing: 1] [Reference Citation Analysis (0)] |
| 37. | Dereddy N, Huang J, Erb M, Guzel S, Wolk JH, Sett SS, Gewitz MH, Mathew R. Associated inflammation or increased flow-mediated shear stress, but not pressure alone, disrupts endothelial caveolin-1 in infants with pulmonary hypertension. Pulm Circ. 2012;2:492-500. [PubMed] [DOI] [Cited in This Article: ] [Cited by in F6Publishing: 1] [Reference Citation Analysis (0)] |
| 38. | Takano H, Komuro I. Peroxisome proliferator-activated receptor gamma and cardiovascular diseases. Circ J. 2009;73:214-220. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 62] [Cited by in F6Publishing: 64] [Article Influence: 4.3] [Reference Citation Analysis (0)] |
| 39. | Harrington LS, Moreno L, Reed A, Wort SJ, Desvergne B, Garland C, Zhao L, Mitchell JA. The PPARbeta/delta agonist GW0742 relaxes pulmonary vessels and limits right heart hypertrophy in rats with hypoxia-induced pulmonary hypertension. PLoS One. 2010;5:e9526. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 36] [Cited by in F6Publishing: 38] [Article Influence: 2.7] [Reference Citation Analysis (0)] |
| 40. | Marx N, Mach F, Sauty A, Leung JH, Sarafi MN, Ransohoff RM, Libby P, Plutzky J, Luster AD. Peroxisome proliferator-activated receptor-gamma activators inhibit IFN-gamma-induced expression of the T cell-active CXC chemokines IP-10, Mig, and I-TAC in human endothelial cells. J Immunol. 2000;164:6503-6508. [PubMed] [Cited in This Article: ] |
| 41. | Pasceri V, Wu HD, Willerson JT, Yeh ET. Modulation of vascular inflammation in vitro and in vivo by peroxisome proliferator-activated receptor-gamma activators. Circulation. 2000;101:235-238. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 401] [Cited by in F6Publishing: 394] [Article Influence: 16.4] [Reference Citation Analysis (0)] |
| 42. | Calnek DS, Mazzella L, Roser S, Roman J, Hart CM. Peroxisome proliferator-activated receptor gamma ligands increase release of nitric oxide from endothelial cells. Arterioscler Thromb Vasc Biol. 2003;23:52-57. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 227] [Cited by in F6Publishing: 232] [Article Influence: 11.0] [Reference Citation Analysis (0)] |
| 43. | Hwang J, Kleinhenz DJ, Lassègue B, Griendling KK, Dikalov S, Hart CM. Peroxisome proliferator-activated receptor-gamma ligands regulate endothelial membrane superoxide production. Am J Physiol Cell Physiol. 2005;288:C899-C905. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 203] [Cited by in F6Publishing: 213] [Article Influence: 10.7] [Reference Citation Analysis (0)] |
| 44. | Law RE, Goetze S, Xi XP, Jackson S, Kawano Y, Demer L, Fishbein MC, Meehan WP, Hsueh WA. Expression and function of PPARgamma in rat and human vascular smooth muscle cells. Circulation. 2000;101:1311-1318. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 330] [Cited by in F6Publishing: 322] [Article Influence: 13.4] [Reference Citation Analysis (0)] |
| 45. | Yang HM, Kim BK, Kim JY, Kwon YW, Jin S, Lee JE, Cho HJ, Lee HY, Kang HJ, Oh BH. PPARγ modulates vascular smooth muscle cell phenotype via a protein kinase G-dependent pathway and reduces neointimal hyperplasia after vascular injury. Exp Mol Med. 2013;45:e65. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 30] [Cited by in F6Publishing: 28] [Article Influence: 2.5] [Reference Citation Analysis (0)] |
| 46. | Ameshima S, Golpon H, Cool CD, Chan D, Vandivier RW, Gardai SJ, Wick M, Nemenoff RA, Geraci MW, Voelkel NF. Peroxisome proliferator-activated receptor gamma (PPARgamma) expression is decreased in pulmonary hypertension and affects endothelial cell growth. Circ Res. 2003;92:1162-1169. [PubMed] [DOI] [Cited in This Article: ] [Cited by in F6Publishing: 1] [Reference Citation Analysis (0)] |
| 47. | Tian J, Smith A, Nechtman J, Podolsky R, Aggarwal S, Snead C, Kumar S, Elgaish M, Oishi P, Göerlach A. Effect of PPARgamma inhibition on pulmonary endothelial cell gene expression: gene profiling in pulmonary hypertension. Physiol Genomics. 2009;40:48-60. [PubMed] [DOI] [Cited in This Article: ] [Cited by in F6Publishing: 1] [Reference Citation Analysis (0)] |
| 48. | Nisbet RE, Bland JM, Kleinhenz DJ, Mitchell PO, Walp ER, Sutliff RL, Hart CM. Rosiglitazone attenuates chronic hypoxia-induced pulmonary hypertension in a mouse model. Am J Respir Cell Mol Biol. 2010;42:482-490. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 147] [Cited by in F6Publishing: 160] [Article Influence: 10.7] [Reference Citation Analysis (0)] |
| 49. | Marx N, Bourcier T, Sukhova GK, Libby P, Plutzky J. PPARgamma activation in human endothelial cells increases plasminogen activator inhibitor type-1 expression: PPARgamma as a potential mediator in vascular disease. Arterioscler Thromb Vasc Biol. 1999;19:546-551. [PubMed] [Cited in This Article: ] |
| 50. | Ho-Tin-Noé B, Le Dall J, Gomez D, Louedec L, Vranckx R, El-Bouchtaoui M, Legrès L, Meilhac O, Michel JB. Early atheroma-derived agonists of peroxisome proliferator-activated receptor-γ trigger intramedial angiogenesis in a smooth muscle cell-dependent manner. Circ Res. 2011;109:1003-1014. [PubMed] [DOI] [Cited in This Article: ] [Cited by in F6Publishing: 1] [Reference Citation Analysis (0)] |
| 51. | Burgermeister E, Tencer L, Liscovitch M. Peroxisome proliferator-activated receptor-gamma upregulates caveolin-1 and caveolin-2 expression in human carcinoma cells. Oncogene. 2003;22:3888-3900. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 75] [Cited by in F6Publishing: 81] [Article Influence: 3.9] [Reference Citation Analysis (0)] |
| 52. | Zaytseva YY, Wallis NK, Southard RC, Kilgore MW. The PPARgamma antagonist T0070907 suppresses breast cancer cell proliferation and motility via both PPARgamma-dependent and -independent mechanisms. Anticancer Res. 2011;31:813-823. [PubMed] [Cited in This Article: ] |
| 53. | Archer SL, Fang YH, Ryan JJ, Piao L. Metabolism and bioenergetics in the right ventricle and pulmonary vasculature in pulmonary hypertension. Pulm Circ. 2013;3:144-152. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 116] [Cited by in F6Publishing: 128] [Article Influence: 11.6] [Reference Citation Analysis (0)] |
| 54. | Xu W, Koeck T, Lara AR, Neumann D, DiFilippo FP, Koo M, Janocha AJ, Masri FA, Arroliga AC, Jennings C. Alterations of cellular bioenergetics in pulmonary artery endothelial cells. Proc Natl Acad Sci USA. 2007;104:1342-1347. [PubMed] [Cited in This Article: ] |
| 55. | Yu Y, Platoshyn O, Zhang J, Krick S, Zhao Y, Rubin LJ, Rothman A, Yuan JX. c-Jun decreases voltage-gated K(+) channel activity in pulmonary artery smooth muscle cells. Circulation. 2001;104:1557-1563. [PubMed] [Cited in This Article: ] |
| 56. | Shiroto T, Romero N, Sugiyama T, Sartoretto JL, Kalwa H, Yan Z, Shimokawa H, Michel T. Caveolin-1 is a critical determinant of autophagy, metabolic switching, and oxidative stress in vascular endothelium. PLoS One. 2014;9:e87871. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 90] [Cited by in F6Publishing: 93] [Article Influence: 9.3] [Reference Citation Analysis (0)] |
| 57. | Pak O, Sommer N, Hoeres T, Bakr A, Waisbrod S, Sydykov A, Haag D, Esfandiary A, Kojonazarov B, Veit F. Mitochondrial hyperpolarization in pulmonary vascular remodeling. Mitochondrial uncoupling protein deficiency as disease model. Am J Respir Cell Mol Biol. 2013;49:358-367. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 56] [Cited by in F6Publishing: 65] [Article Influence: 5.9] [Reference Citation Analysis (0)] |
| 58. | McMurtry MS, Bonnet S, Wu X, Dyck JR, Haromy A, Hashimoto K, Michelakis ED. Dichloroacetate prevents and reverses pulmonary hypertension by inducing pulmonary artery smooth muscle cell apoptosis. Circ Res. 2004;95:830-840. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 353] [Cited by in F6Publishing: 349] [Article Influence: 17.5] [Reference Citation Analysis (0)] |
| 59. | Maenhaut N, Van de Voorde J. Regulation of vascular tone by adipocytes. BMC Med. 2011;9:25. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 101] [Cited by in F6Publishing: 103] [Article Influence: 7.9] [Reference Citation Analysis (0)] |
| 60. | Zechner R, Moser R, Newman TC, Fried SK, Breslow JL. Apolipoprotein E gene expression in mouse 3T3-L1 adipocytes and human adipose tissue and its regulation by differentiation and lipid content. J Biol Chem. 1991;266:10583-10588. [PubMed] [Cited in This Article: ] |
| 61. | Löhn M, Dubrovska G, Lauterbach B, Luft FC, Gollasch M, Sharma AM. Periadventitial fat releases a vascular relaxing factor. FASEB J. 2002;16:1057-1063. [PubMed] [DOI] [Cited in This Article: ] [Cited by in F6Publishing: 1] [Reference Citation Analysis (0)] |
| 62. | Chang L, Villacorta L, Li R, Hamblin M, Xu W, Dou C, Zhang J, Wu J, Zeng R, Chen YE. Loss of perivascular adipose tissue on peroxisome proliferator-activated receptor-γ deletion in smooth muscle cells impairs intravascular thermoregulation and enhances atherosclerosis. Circulation. 2012;126:1067-1078. [PubMed] [DOI] [Cited in This Article: ] [Cited by in F6Publishing: 1] [Reference Citation Analysis (0)] |
| 63. | Komura N, Maeda N, Mori T, Kihara S, Nakatsuji H, Hirata A, Tochino Y, Funahashi T, Shimomura I. Adiponectin protein exists in aortic endothelial cells. PLoS One. 2013;8:e71271. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 35] [Cited by in F6Publishing: 37] [Article Influence: 3.4] [Reference Citation Analysis (0)] |
| 64. | Nishimura M, Izumiya Y, Higuchi A, Shibata R, Qiu J, Kudo C, Shin HK, Moskowitz MA, Ouchi N. Adiponectin prevents cerebral ischemic injury through endothelial nitric oxide synthase dependent mechanisms. Circulation. 2008;117:216-223. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 158] [Cited by in F6Publishing: 160] [Article Influence: 9.4] [Reference Citation Analysis (0)] |
| 65. | Ohashi K, Kihara S, Ouchi N, Kumada M, Fujita K, Hiuge A, Hibuse T, Ryo M, Nishizawa H, Maeda N. Adiponectin replenishment ameliorates obesity-related hypertension. Hypertension. 2006;47:1108-1116. [PubMed] [Cited in This Article: ] |
| 66. | Xi W, Satoh H, Kase H, Suzuki K, Hattori Y. Stimulated HSP90 binding to eNOS and activation of the PI3-Akt pathway contribute to globular adiponectin-induced NO production: vasorelaxation in response to globular adiponectin. Biochem Biophys Res Commun. 2005;332:200-205. [PubMed] [DOI] [Cited in This Article: ] [Cited by in F6Publishing: 1] [Reference Citation Analysis (0)] |
| 67. | Kobayashi H, Ouchi N, Kihara S, Walsh K, Kumada M, Abe Y, Funahashi T, Matsuzawa Y. Selective suppression of endothelial cell apoptosis by the high molecular weight form of adiponectin. Circ Res. 2004;94:e27-e31. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 486] [Cited by in F6Publishing: 512] [Article Influence: 25.6] [Reference Citation Analysis (0)] |
| 68. | Margaritis M, Antonopoulos AS, Digby J, Lee R, Reilly S, Coutinho P, Shirodaria C, Sayeed R, Petrou M, De Silva R. Interactions between vascular wall and perivascular adipose tissue reveal novel roles for adiponectin in the regulation of endothelial nitric oxide synthase function in human vessels. Circulation. 2013;127:2209-2221. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 204] [Cited by in F6Publishing: 236] [Article Influence: 21.5] [Reference Citation Analysis (0)] |
| 69. | Meijer RI, Bakker W, Alta CL, Sipkema P, Yudkin JS, Viollet B, Richter EA, Smulders YM, van Hinsbergh VW, Serné EH. Perivascular adipose tissue control of insulin-induced vasoreactivity in muscle is impaired in db/db mice. Diabetes. 2013;62:590-598. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 91] [Cited by in F6Publishing: 97] [Article Influence: 8.8] [Reference Citation Analysis (0)] |
| 70. | Takaoka M, Nagata D, Kihara S, Shimomura I, Kimura Y, Tabata Y, Saito Y, Nagai R, Sata M. Periadventitial adipose tissue plays a critical role in vascular remodeling. Circ Res. 2009;105:906-911. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 147] [Cited by in F6Publishing: 155] [Article Influence: 10.3] [Reference Citation Analysis (0)] |
| 71. | Summer R, Fiack CA, Ikeda Y, Sato K, Dwyer D, Ouchi N, Fine A, Farber HW, Walsh K. Adiponectin deficiency: a model of pulmonary hypertension associated with pulmonary vascular disease. Am J Physiol Lung Cell Mol Physiol. 2009;297:L432-L438. [PubMed] [DOI] [Cited in This Article: ] [Cited by in F6Publishing: 1] [Reference Citation Analysis (0)] |
| 72. | Ran J, Xiong X, Liu W, Guo S, Li Q, Zhang R, Lao G. Increased plasma adiponectin closely associates with vascular endothelial dysfunction in type 2 diabetic patients with diabetic nephropathy. Diabetes Res Clin Pract. 2010;88:177-183. [PubMed] [DOI] [Cited in This Article: ] [Cited by in F6Publishing: 2] [Reference Citation Analysis (0)] |
| 73. | Mantzoros CS, Magkos F, Brinkoetter M, Sienkiewicz E, Dardeno TA, Kim SY, Hamnvik OP, Koniaris A. Leptin in human physiology and pathophysiology. Am J Physiol Endocrinol Metab. 2011;301:E567-E584. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 381] [Cited by in F6Publishing: 372] [Article Influence: 28.6] [Reference Citation Analysis (0)] |
| 74. | Taleb S, Herbin O, Ait-Oufella H, Verreth W, Gourdy P, Barateau V, Merval R, Esposito B, Clément K, Holvoet P. Defective leptin/leptin receptor signaling improves regulatory T cell immune response and protects mice from atherosclerosis. Arterioscler Thromb Vasc Biol. 2007;27:2691-2698. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 111] [Cited by in F6Publishing: 114] [Article Influence: 8.8] [Reference Citation Analysis (0)] |
| 75. | Eller K, Kirsch A, Wolf AM, Sopper S, Tagwerker A, Stanzl U, Wolf D, Patsch W, Rosenkranz AR, Eller P. Potential role of regulatory T cells in reversing obesity-linked insulin resistance and diabetic nephropathy. Diabetes. 2011;60:2954-2962. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 111] [Cited by in F6Publishing: 114] [Article Influence: 8.8] [Reference Citation Analysis (0)] |
| 76. | Matarese G, Carrieri PB, La Cava A, Perna F, Sanna V, De Rosa V, Aufiero D, Fontana S, Zappacosta S. Leptin increase in multiple sclerosis associates with reduced number of CD4(+)CD25+ regulatory T cells. Proc Natl Acad Sci USA. 2005;102:5150-5155. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 228] [Cited by in F6Publishing: 218] [Article Influence: 11.5] [Reference Citation Analysis (0)] |
| 77. | Gálvez-Prieto B, Somoza B, Gil-Ortega M, García-Prieto CF, de Las Heras AI, González MC, Arribas S, Aranguez I, Bolbrinker J, Kreutz R. Anticontractile Effect of Perivascular Adipose Tissue and Leptin are Reduced in Hypertension. Front Pharmacol. 2012;3:103. [PubMed] [DOI] [Cited in This Article: ] [Cited by in F6Publishing: 12] [Reference Citation Analysis (0)] |
| 78. | Schroeter MR, Eschholz N, Herzberg S, Jerchel I, Leifheit-Nestler M, Czepluch FS, Chalikias G, Konstantinides S, Schäfer K. Leptin-dependent and leptin-independent paracrine effects of perivascular adipose tissue on neointima formation. Arterioscler Thromb Vasc Biol. 2013;33:980-987. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 50] [Cited by in F6Publishing: 51] [Article Influence: 4.6] [Reference Citation Analysis (0)] |
| 79. | Oda A, Taniguchi T, Yokoyama M. Leptin stimulates rat aortic smooth muscle cell proliferation and migration. Kobe J Med Sci. 2001;47:141-150. [PubMed] [Cited in This Article: ] |
| 80. | Huertas A, Tu L, Gambaryan N, Girerd B, Perros F, Montani D, Fabre D, Fadel E, Eddahibi S, Cohen-Kaminsky S. Leptin and regulatory T-lymphocytes in idiopathic pulmonary arterial hypertension. Eur Respir J. 2012;40:895-904. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 83] [Cited by in F6Publishing: 85] [Article Influence: 7.1] [Reference Citation Analysis (0)] |
| 81. | Hofmann SM, Perez-Tilve D, Greer TM, Coburn BA, Grant E, Basford JE, Tschöp MH, Hui DY. Defective lipid delivery modulates glucose tolerance and metabolic response to diet in apolipoprotein E-deficient mice. Diabetes. 2008;57:5-12. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 77] [Cited by in F6Publishing: 77] [Article Influence: 4.8] [Reference Citation Analysis (0)] |
| 82. | Huang ZH, Gu D, Mazzone T. Role of adipocyte-derived apoE in modulating adipocyte size, lipid metabolism, and gene expression in vivo. Am J Physiol Endocrinol Metab. 2009;296:E1110-E1119. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 34] [Cited by in F6Publishing: 38] [Article Influence: 2.5] [Reference Citation Analysis (0)] |
| 83. | Yue L, Mazzone T. Endogenous adipocyte apolipoprotein E is colocalized with caveolin at the adipocyte plasma membrane. J Lipid Res. 2011;52:489-498. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 19] [Cited by in F6Publishing: 21] [Article Influence: 1.5] [Reference Citation Analysis (0)] |
| 84. | Stannard AK, Riddell DR, Sacre SM, Tagalakis AD, Langer C, von Eckardstein A, Cullen P, Athanasopoulos T, Dickson G, Owen JS. Cell-derived apolipoprotein E (ApoE) particles inhibit vascular cell adhesion molecule-1 (VCAM-1) expression in human endothelial cells. J Biol Chem. 2001;276:46011-46016. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 64] [Cited by in F6Publishing: 69] [Article Influence: 3.0] [Reference Citation Analysis (0)] |
| 85. | Yue L, Bian JT, Grizelj I, Cavka A, Phillips SA, Makino A, Mazzone T. Apolipoprotein E enhances endothelial-NO production by modulating caveolin 1 interaction with endothelial NO synthase. Hypertension. 2012;60:1040-1046. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 27] [Cited by in F6Publishing: 30] [Article Influence: 2.5] [Reference Citation Analysis (0)] |
| 86. | Frank PG, Lee H, Park DS, Tandon NN, Scherer PE, Lisanti MP. Genetic ablation of caveolin-1 confers protection against atherosclerosis. Arterioscler Thromb Vasc Biol. 2004;24:98-105. [PubMed] [Cited in This Article: ] |
| 87. | Hu Q, Zhang XJ, Liu CX, Wang XP, Zhang Y. PPARgamma1-induced caveolin-1 enhances cholesterol efflux and attenuates atherosclerosis in apolipoprotein E-deficient mice. J Vasc Res. 2010;47:69-79. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 29] [Cited by in F6Publishing: 33] [Article Influence: 2.2] [Reference Citation Analysis (0)] |
| 88. | Hansmann G, Wagner RA, Schellong S, Perez VA, Urashima T, Wang L, Sheikh AY, Suen RS, Stewart DJ, Rabinovitch M. Pulmonary arterial hypertension is linked to insulin resistance and reversed by peroxisome proliferator-activated receptor-gamma activation. Circulation. 2007;115:1275-1284. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 297] [Cited by in F6Publishing: 295] [Article Influence: 17.4] [Reference Citation Analysis (0)] |
| 89. | Rosen ED, Spiegelman BM. Adipocytes as regulators of energy balance and glucose homeostasis. Nature. 2006;444:847-853. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 1501] [Cited by in F6Publishing: 1527] [Article Influence: 89.8] [Reference Citation Analysis (0)] |
| 90. | Farmer SR. Transcriptional control of adipocyte formation. Cell Metab. 2006;4:263-273. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 1423] [Cited by in F6Publishing: 1370] [Article Influence: 76.1] [Reference Citation Analysis (0)] |
| 91. | Tilg H, Moschen AR. Adipocytokines: mediators linking adipose tissue, inflammation and immunity. Nat Rev Immunol. 2006;6:772-783. [PubMed] [Cited in This Article: ] |
| 92. | Wagner M, Dudley AC. A three-party alliance in solid tumors: Adipocytes, macrophages and vascular endothelial cells. Adipocyte. 2013;2:67-73. [PubMed] [Cited in This Article: ] |
| 93. | Grundy SM, Brewer HB, Cleeman JI, Smith SC, Lenfant C. Definition of metabolic syndrome: Report of the National Heart, Lung, and Blood Institute/American Heart Association conference on scientific issues related to definition. Circulation. 2004;109:433-438. [PubMed] [DOI] [Cited in This Article: ] [Cited by in F6Publishing: 1] [Reference Citation Analysis (0)] |
| 94. | Hagberg CE, Falkevall A, Wang X, Larsson E, Huusko J, Nilsson I, van Meeteren LA, Samen E, Lu L, Vanwildemeersch M. Vascular endothelial growth factor B controls endothelial fatty acid uptake. Nature. 2010;464:917-921. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 342] [Cited by in F6Publishing: 353] [Article Influence: 25.2] [Reference Citation Analysis (0)] |
| 95. | Hagberg CE, Mehlem A, Falkevall A, Muhl L, Fam BC, Ortsäter H, Scotney P, Nyqvist D, Samén E, Lu L. Targeting VEGF-B as a novel treatment for insulin resistance and type 2 diabetes. Nature. 2012;490:426-430. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 207] [Cited by in F6Publishing: 212] [Article Influence: 17.7] [Reference Citation Analysis (0)] |
| 96. | Karpanen T, Bry M, Ollila HM, Seppänen-Laakso T, Liimatta E, Leskinen H, Kivelä R, Helkamaa T, Merentie M, Jeltsch M. Overexpression of vascular endothelial growth factor-B in mouse heart alters cardiac lipid metabolism and induces myocardial hypertrophy. Circ Res. 2008;103:1018-1026. [PubMed] [DOI] [Cited in This Article: ] [Cited by in F6Publishing: 1] [Reference Citation Analysis (0)] |
| 97. | Mehrotra D, Wu J, Papangeli I, Chun HJ. Endothelium as a gatekeeper of fatty acid transport. Trends Endocrinol Metab. 2014;25:99-106. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 40] [Cited by in F6Publishing: 44] [Article Influence: 4.4] [Reference Citation Analysis (0)] |
| 98. | Cohen AW, Combs TP, Scherer PE, Lisanti MP. Role of caveolin and caveolae in insulin signaling and diabetes. Am J Physiol Endocrinol Metab. 2003;285:E1151-E1160. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 147] [Cited by in F6Publishing: 153] [Article Influence: 7.3] [Reference Citation Analysis (0)] |
| 99. | Yamamoto M, Toya Y, Schwencke C, Lisanti MP, Myers MG, Ishikawa Y. Caveolin is an activator of insulin receptor signaling. J Biol Chem. 1998;273:26962-26968. [PubMed] [Cited in This Article: ] |
| 100. | Ros-Baro A, Lopez-Iglesias C, Peiro S, Bellido D, Palacin M, Zorzano A, Camps M. Lipid rafts are required for GLUT4 internalization in adipose cells. Proc Natl Acad Sci U S A. 2001;98:12050-12055. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 117] [Cited by in F6Publishing: 121] [Article Influence: 5.3] [Reference Citation Analysis (0)] |
| 101. | Scherer PE, Lisanti MP, Baldini G, Sargiacomo M, Mastick CC, Lodish HF. Induction of caveolin during adipogenesis and association of GLUT4 with caveolin-rich vesicles. J Cell Biol. 1994;127:1233-1243. [PubMed] [Cited in This Article: ] |
| 102. | Singh P, Peterson TE, Sert-Kuniyoshi FH, Glenn JA, Davison DE, Romero-Corral A, Pusalavidyasagar S, Jensen MD, Somers VK. Leptin signaling in adipose tissue: role in lipid accumulation and weight gain. Circ Res. 2012;111:599-603. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 26] [Cited by in F6Publishing: 28] [Article Influence: 2.3] [Reference Citation Analysis (0)] |
| 103. | Singh P, Peterson TE, Sert-Kuniyoshi FH, Jensen MD, Somers VK. Leptin upregulates caveolin-1 expression: implications for development of atherosclerosis. Atherosclerosis. 2011;217:499-502. [PubMed] [DOI] [Cited in This Article: ] [Cited by in F6Publishing: 1] [Reference Citation Analysis (0)] |
| 104. | Catalán V, Gómez-Ambrosi J, Rodríguez A, Silva C, Rotellar F, Gil MJ, Cienfuegos JA, Salvador J, Frühbeck G. Expression of caveolin-1 in human adipose tissue is upregulated in obesity and obesity-associated type 2 diabetes mellitus and related to inflammation. Clin Endocrinol (Oxf). 2008;68:213-219. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 19] [Cited by in F6Publishing: 55] [Article Influence: 3.4] [Reference Citation Analysis (0)] |
| 105. | Lam TY, Seto SW, Lau YM, Au LS, Kwan YW, Ngai SM, Tsui KW. Impairment of the vascular relaxation and differential expression of caveolin-1 of the aorta of diabetic +db/+db mice. Eur J Pharmacol. 2006;546:134-141. [PubMed] [Cited in This Article: ] |
| 106. | Murata T, Sato K, Hori M, Ozaki H, Karaki H. Decreased endothelial nitric-oxide synthase (eNOS) activity resulting from abnormal interaction between eNOS and its regulatory proteins in hypoxia-induced pulmonary hypertension. J Biol Chem. 2002;277:44085-44092. [PubMed] [DOI] [Cited in This Article: ] [Cited by in F6Publishing: 1] [Reference Citation Analysis (0)] |
| 107. | Ost A, Ortegren U, Gustavsson J, Nystrom FH, Strålfors P. Triacylglycerol is synthesized in a specific subclass of caveolae in primary adipocytes. J Biol Chem. 2005;280:5-8. [PubMed] [DOI] [Cited in This Article: ] [Cited by in F6Publishing: 1] [Reference Citation Analysis (0)] |
| 108. | Cohen AW, Razani B, Schubert W, Williams TM, Wang XB, Iyengar P, Brasaemle DL, Scherer PE, Lisanti MP. Role of caveolin-1 in the modulation of lipolysis and lipid droplet formation. Diabetes. 2004;53:1261-1270. [PubMed] [DOI] [Cited in This Article: ] [Cited by in F6Publishing: 1] [Reference Citation Analysis (0)] |
| 109. | Le Lay S, Hajduch E, Lindsay MR, Le Lièpvre X, Thiele C, Ferré P, Parton RG, Kurzchalia T, Simons K, Dugail I. Cholesterol-induced caveolin targeting to lipid droplets in adipocytes: a role for caveolar endocytosis. Traffic. 2006;7:549-561. [PubMed] [DOI] [Cited in This Article: ] [Cited by in F6Publishing: 2] [Reference Citation Analysis (0)] |
| 110. | Frank PG, Pavlides S, Cheung MW, Daumer K, Lisanti MP. Role of caveolin-1 in the regulation of lipoprotein metabolism. Am J Physiol Cell Physiol. 2008;295:C242-C248. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 98] [Cited by in F6Publishing: 105] [Article Influence: 6.6] [Reference Citation Analysis (0)] |
| 111. | Kim CA, Delépine M, Boutet E, El Mourabit H, Le Lay S, Meier M, Nemani M, Bridel E, Leite CC, Bertola DR. Association of a homozygous nonsense caveolin-1 mutation with Berardinelli-Seip congenital lipodystrophy. J Clin Endocrinol Metab. 2008;93:1129-1134. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 308] [Cited by in F6Publishing: 278] [Article Influence: 17.4] [Reference Citation Analysis (0)] |
| 112. | Cao H, Alston L, Ruschman J, Hegele RA. Heterozygous CAV1 frameshift mutations (MIM 601047) in patients with atypical partial lipodystrophy and hypertriglyceridemia. Lipids Health Dis. 2008;7:3. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 100] [Cited by in F6Publishing: 108] [Article Influence: 6.8] [Reference Citation Analysis (0)] |
| 113. | Hayashi YK, Matsuda C, Ogawa M, Goto K, Tominaga K, Mitsuhashi S, Park YE, Nonaka I, Hino-Fukuyo N, Haginoya K. Human PTRF mutations cause secondary deficiency of caveolins resulting in muscular dystrophy with generalized lipodystrophy. J Clin Invest. 2009;119:2623-2633. [PubMed] [Cited in This Article: ] |
| 114. | Asterholm IW, Mundy DI, Weng J, Anderson RG, Scherer PE. Altered mitochondrial function and metabolic inflexibility associated with loss of caveolin-1. Cell Metab. 2012;15:171-185. [PubMed] [Cited in This Article: ] |
| 115. | Martin S, Fernandez-Rojo MA, Stanley AC, Bastiani M, Okano S, Nixon SJ, Thomas G, Stow JL, Parton RG. Caveolin-1 deficiency leads to increased susceptibility to cell death and fibrosis in white adipose tissue: characterization of a lipodystrophic model. PLoS One. 2012;7:e46242. [PubMed] [DOI] [Cited in This Article: ] [Cited by in F6Publishing: 1] [Reference Citation Analysis (0)] |
| 116. | Briand N, Le Lay S, Sessa WC, Ferré P, Dugail I. Distinct roles of endothelial and adipocyte caveolin-1 in macrophage infiltration and adipose tissue metabolic activity. Diabetes. 2011;60:448-453. [PubMed] [Cited in This Article: ] |
| 117. | Rosen ED, Sarraf P, Troy AE, Bradwin G, Moore K, Milstone DS, Spiegelman BM, Mortensen RM. PPAR gamma is required for the differentiation of adipose tissue in vivo and in vitro. Mol Cell. 1999;4:611-617. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 1516] [Cited by in F6Publishing: 1511] [Article Influence: 60.4] [Reference Citation Analysis (0)] |
| 118. | Norris AW, Chen L, Fisher SJ, Szanto I, Ristow M, Jozsi AC, Hirshman MF, Rosen ED, Goodyear LJ, Gonzalez FJ. Muscle-specific PPARgamma-deficient mice develop increased adiposity and insulin resistance but respond to thiazolidinediones. J Clin Invest. 2003;112:608-618. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 308] [Cited by in F6Publishing: 312] [Article Influence: 14.9] [Reference Citation Analysis (0)] |
| 119. | Nicol CJ, Adachi M, Akiyama TE, Gonzalez FJ. PPARgamma in endothelial cells influences high fat diet-induced hypertension. Am J Hypertens. 2005;18:549-556. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 78] [Cited by in F6Publishing: 85] [Article Influence: 4.5] [Reference Citation Analysis (0)] |
| 120. | Ristow M, Müller-Wieland D, Pfeiffer A, Krone W, Kahn CR. Obesity associated with a mutation in a genetic regulator of adipocyte differentiation. N Engl J Med. 1998;339:953-959. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 382] [Cited by in F6Publishing: 400] [Article Influence: 15.4] [Reference Citation Analysis (0)] |
| 121. | Barroso I, Gurnell M, Crowley VE, Agostini M, Schwabe JW, Soos MA, Maslen GL, Williams TD, Lewis H, Schafer AJ. Dominant negative mutations in human PPARgamma associated with severe insulin resistance, diabetes mellitus and hypertension. Nature. 1999;402:880-883. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 1027] [Cited by in F6Publishing: 942] [Article Influence: 37.7] [Reference Citation Analysis (0)] |
| 122. | Auclair M, Vigouroux C, Boccara F, Capel E, Vigeral C, Guerci B, Lascols O, Capeau J, Caron-Debarle M. Peroxisome proliferator-activated receptor-γ mutations responsible for lipodystrophy with severe hypertension activate the cellular renin-angiotensin system. Arterioscler Thromb Vasc Biol. 2013;33:829-838. [PubMed] [DOI] [Cited in This Article: ] [Cited by in F6Publishing: 1] [Reference Citation Analysis (0)] |
| 123. | Wei J, Bhattacharyya S, Jain M, Varga J. Regulation of Matrix Remodeling by Peroxisome Proliferator-Activated Receptor-γ: A Novel Link Between Metabolism and Fibrogenesis. Open Rheumatol J. 2012;6:103-115. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 39] [Cited by in F6Publishing: 39] [Article Influence: 3.3] [Reference Citation Analysis (0)] |
| 124. | Handy JA, Fu PP, Kumar P, Mells JE, Sharma S, Saxena NK, Anania FA. Adiponectin inhibits leptin signalling via multiple mechanisms to exert protective effects against hepatic fibrosis. Biochem J. 2011;440:385-395. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 66] [Cited by in F6Publishing: 74] [Article Influence: 6.2] [Reference Citation Analysis (0)] |
| 125. | Nakagawa Y, Kishida K, Kihara S, Funahashi T, Shimomura I. Adiponectin ameliorates hypoxia-induced pulmonary arterial remodeling. Biochem Biophys Res Commun. 2009;382:183-188. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 27] [Cited by in F6Publishing: 30] [Article Influence: 2.0] [Reference Citation Analysis (0)] |
| 126. | Jain M, Budinger GR, Lo A, Urich D, Rivera SE, Ghosh AK, Gonzalez A, Chiarella SE, Marks K, Donnelly HK. Leptin promotes fibroproliferative acute respiratory distress syndrome by inhibiting peroxisome proliferator-activated receptor-γ. Am J Respir Crit Care Med. 2011;183:1490-1498. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 71] [Cited by in F6Publishing: 77] [Article Influence: 5.9] [Reference Citation Analysis (0)] |
| 127. | Monsalve FA, Pyarasani RD, Delgado-Lopez F, Moore-Carrasco R. Peroxisome proliferator-activated receptor targets for the treatment of metabolic diseases. Mediators Inflamm. 2013;2013:549627. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 240] [Cited by in F6Publishing: 233] [Article Influence: 21.2] [Reference Citation Analysis (0)] |
| 128. | Yamauchi T, Kamon J, Waki H, Terauchi Y, Kubota N, Hara K, Mori Y, Ide T, Murakami K, Tsuboyama-Kasaoka N. The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med. 2001;7:941-946. [PubMed] [Cited in This Article: ] |
| 129. | Nesto RW, Bell D, Bonow RO, Fonseca V, Grundy SM, Horton ES, Le Winter M, Porte D, Semenkovich CF, Smith S. Thiazolidinedione use, fluid retention, and congestive heart failure: a consensus statement from the American Heart Association and American Diabetes Association. Diabetes Care. 2004;27:256-263. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 625] [Cited by in F6Publishing: 653] [Article Influence: 32.7] [Reference Citation Analysis (0)] |
| 130. | Martens FM, Rabelink TJ, op ‘t Roodt J, de Koning EJ, Visseren FL. TNF-alpha induces endothelial dysfunction in diabetic adults, an effect reversible by the PPAR-gamma agonist pioglitazone. Eur Heart J. 2006;27:1605-1609. [PubMed] [DOI] [Cited in This Article: ] |
| 131. | Duan SZ, Ivashchenko CY, Russell MW, Milstone DS, Mortensen RM. Cardiomyocyte-specific knockout and agonist of peroxisome proliferator-activated receptor-gamma both induce cardiac hypertrophy in mice. Circ Res. 2005;97:372-379. [PubMed] [Cited in This Article: ] |
| 132. | Lee DH, Huang H, Choi K, Mantzoros C, Kim YB. Selective PPARγ modulator INT131 normalizes insulin signaling defects and improves bone mass in diet-induced obese mice. Am J Physiol Endocrinol Metab. 2012;302:E552-E560. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 35] [Cited by in F6Publishing: 37] [Article Influence: 3.1] [Reference Citation Analysis (0)] |
| 133. | McQuillan BM, Picard MH, Leavitt M, Weyman AE. Clinical correlates and reference intervals for pulmonary artery systolic pressure among echocardiographically normal subjects. Circulation. 2001;104:2797-2802. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 437] [Cited by in F6Publishing: 429] [Article Influence: 18.7] [Reference Citation Analysis (0)] |
| 134. | Robbins IM, Newman JH, Johnson RF, Hemnes AR, Fremont RD, Piana RN, Zhao DX, Byrne DW. Association of the metabolic syndrome with pulmonary venous hypertension. Chest. 2009;136:31-36. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 125] [Cited by in F6Publishing: 130] [Article Influence: 8.7] [Reference Citation Analysis (0)] |
| 135. | Leung CC, Moondra V, Catherwood E, Andrus BW. Prevalence and risk factors of pulmonary hypertension in patients with elevated pulmonary venous pressure and preserved ejection fraction. Am J Cardiol. 2010;106:284-286. [PubMed] [DOI] [Cited in This Article: ] [Cited by in F6Publishing: 1] [Reference Citation Analysis (0)] |
| 136. | Movahed MR, Hashemzadeh M, Jamal MM. The prevalence of pulmonary embolism and pulmonary hypertension in patients with type II diabetes mellitus. Chest. 2005;128:3568-3571. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 13] [Cited by in F6Publishing: 36] [Article Influence: 1.9] [Reference Citation Analysis (0)] |
| 137. | Zamanian RT, Hansmann G, Snook S, Lilienfeld D, Rappaport KM, Reaven GM, Rabinovitch M, Doyle RL. Insulin resistance in pulmonary arterial hypertension. Eur Respir J. 2009;33:318-324. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 189] [Cited by in F6Publishing: 200] [Article Influence: 12.5] [Reference Citation Analysis (0)] |
| 138. | Shapiro S, Traiger GL, Turner M, McGoon MD, Wason P, Barst RJ. Sex differences in the diagnosis, treatment, and outcome of patients with pulmonary arterial hypertension enrolled in the registry to evaluate early and long-term pulmonary arterial hypertension disease management. Chest. 2012;141:363-373. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 121] [Cited by in F6Publishing: 118] [Article Influence: 9.1] [Reference Citation Analysis (0)] |
| 139. | Poms AD, Turner M, Farber HW, Meltzer LA, McGoon MD. Comorbid conditions and outcomes in patients with pulmonary arterial hypertension: a REVEAL registry analysis. Chest. 2013;144:169-176. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 90] [Cited by in F6Publishing: 92] [Article Influence: 8.4] [Reference Citation Analysis (0)] |
| 140. | Moral-Sanz J, Lopez-Lopez JG, Menendez C, Moreno E, Barreira B, Morales-Cano D, Escolano L, Fernandez-Segoviano P, Villamor E, Cogolludo A. Different patterns of pulmonary vascular disease induced by type 1 diabetes and moderate hypoxia in rats. Exp Physiol. 2012;97:676-686. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 24] [Cited by in F6Publishing: 25] [Article Influence: 2.1] [Reference Citation Analysis (0)] |
| 141. | Semenza GL. Involvement of hypoxia-inducible factor 1 in pulmonary pathophysiology. Chest. 2005;128:592S-594S. [PubMed] [DOI] [Cited in This Article: ] [Cited by in F6Publishing: 1] [Reference Citation Analysis (0)] |
| 142. | Klimova T, Chandel NS. Mitochondrial complex III regulates hypoxic activation of HIF. Cell Death Differ. 2008;15:660-666. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 285] [Cited by in F6Publishing: 298] [Article Influence: 18.6] [Reference Citation Analysis (0)] |
| 143. | Seagrove T, Ryan HE, Lu H, Wouters BG, Knapp M, Thibault P, Lederoute K, Johnson RS. Transcription factor HIF-1 is a necessary mediator of Pasteur effect in mammalian cells. Mol Cell Biol. 2001;21:3426-3444. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 442] [Cited by in F6Publishing: 445] [Article Influence: 19.3] [Reference Citation Analysis (0)] |
| 144. | Tuder RM, Chacon M, Alger L, Wang J, Taraseviciene-Stewart L, Kasahara Y, Cool CD, Bishop AE, Geraci M, Semenza GL. Expression of angiogenesis-related molecules in plexiform lesions in severe pulmonary hypertension: evidence for a process of disordered angiogenesis. J Pathol. 2001;195:367-374. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 356] [Cited by in F6Publishing: 342] [Article Influence: 14.9] [Reference Citation Analysis (0)] |
| 145. | Ball MK, Waypa GB, Mungai PT, Nielsen JM, Czech L, Dudley VJ, Beussink L, Dettman RW, Berkelhamer SK, Steinhorn RH. Regulation of hypoxia-induced pulmonary hypertension by vascular smooth muscle hypoxia-inducible factor-1α. Am J Respir Crit Care Med. 2014;189:314-324. [PubMed] [DOI] [Cited in This Article: ] [Cited by in F6Publishing: 1] [Reference Citation Analysis (0)] |
| 146. | Wang Y, Roche O, Xu C, Moriyama EH, Heir P, Chung J, Roos FC, Chen Y, Finak G, Milosevic M. Hypoxia promotes ligand-independent EGF receptor signaling via hypoxia-inducible factor-mediated upregulation of caveolin-1. Proc Natl Acad Sci USA. 2012;109:4892-4897. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 97] [Cited by in F6Publishing: 100] [Article Influence: 8.3] [Reference Citation Analysis (0)] |
| 147. | Kim YM, Barnes EA, Alvira CM, Ying L, Reddy S, Cornfield DN. Hypoxia-inducible factor-1α in pulmonary artery smooth muscle cells lowers vascular tone by decreasing myosin light chain phosphorylation. Circ Res. 2013;112:1230-1233. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 49] [Cited by in F6Publishing: 58] [Article Influence: 5.3] [Reference Citation Analysis (0)] |
| 148. | Huang Y, Di Lorenzo A, Jiang W, Cantalupo A, Sessa WC, Giordano FJ. Hypoxia-inducible factor-1α in vascular smooth muscle regulates blood pressure homeostasis through a peroxisome proliferator-activated receptor-γ-angiotensin II receptor type 1 axis. Hypertension. 2013;62:634-640. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 24] [Cited by in F6Publishing: 25] [Article Influence: 2.3] [Reference Citation Analysis (0)] |
| 149. | Wei H, Bedja D, Koitabashi N, Xing D, Chen J, Fox-Talbot K, Rouf R, Chen S, Steenbergen C, Harmon JW. Endothelial expression of hypoxia-inducible factor 1 protects the murine heart and aorta from pressure overload by suppression of TGF-β signaling. Proc Natl Acad Sci USA. 2012;109:E841-E850. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 112] [Cited by in F6Publishing: 103] [Article Influence: 8.6] [Reference Citation Analysis (0)] |
| 150. | Huang Y, Lei L, Liu D, Jovin I, Russell R, Johnson RS, Di Lorenzo A, Giordano FJ. Normal glucose uptake in the brain and heart requires an endothelial cell-specific HIF-1α-dependent function. Proc Natl Acad Sci USA. 2012;109:17478-17483. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 79] [Cited by in F6Publishing: 86] [Article Influence: 7.2] [Reference Citation Analysis (0)] |
| 151. | Catrina SB, Okamoto K, Pereira T, Brismar K, Poellinger L. Hyperglycemia regulates hypoxia-inducible factor-1alpha protein stability and function. Diabetes. 2004;53:3226-3232. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 262] [Cited by in F6Publishing: 269] [Article Influence: 13.5] [Reference Citation Analysis (0)] |
| 152. | Bento CF, Pereira P. Regulation of hypoxia-inducible factor 1 and the loss of the cellular response to hypoxia in diabetes. Diabetologia. 2011;54:1946-1956. [PubMed] [DOI] [Cited in This Article: ] [Cited by in F6Publishing: 1] [Reference Citation Analysis (0)] |
| 153. | Zhang X, Sarkar K, Rey S, Sebastian R, Andrikopoulou E, Marti GP, Fox-Talbot K, Semenza GL, Harmon JW. Aging impairs the mobilization and homing of bone marrow-derived angiogenic cells to burn wounds. J Mol Med (Berl). 2011;89:985-995. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 39] [Cited by in F6Publishing: 43] [Article Influence: 3.3] [Reference Citation Analysis (0)] |
| 154. | Jiang C, Qu A, Matsubara T, Chanturiya T, Jou W, Gavrilova O, Shah YM, Gonzalez FJ. Disruption of hypoxia-inducible factor 1 in adipocytes improves insulin sensitivity and decreases adiposity in high-fat diet-fed mice. Diabetes. 2011;60:2484-2495. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 212] [Cited by in F6Publishing: 209] [Article Influence: 16.1] [Reference Citation Analysis (0)] |