Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids
ReviewPPARα in atherosclerosis and inflammation
Introduction
Atherosclerosis, the major cause of death from cardiovascular disease in industrialized countries, is characterized by the progressive accumulation of lipid and fibrous depositions in the vessel wall of large arteries [1], [2]. Well-established risk factors for atherosclerosis include hypertension, hypercholesterolemia, and diabetes mellitus. More recent work reveals procoagulant and proinflammatory states can be added as important contributors to the development of atherosclerosis [3], [4], [5]. To an increasing extent, attention has focused on how abnormalities of metabolism – atherogenic dyslipidemia, insulin resistance, visceral adiposity – may promote atherogenesis. Indeed, clinical evidence underscores how parameters such as glucose represent a continuous rather than dichotomous variable in cardiovascular risk, even at levels that do not meet a diagnosis of frank diabetes. Likewise, although debates continue regarding triglycerides as an independent risk factor for cardiovascular events, the presence of hypertriglycemia confers a considerable increase in risk among subjects with otherwise similar ratios of low density lipoprotein (LDL) and high density lipoprotein (HDL).
This evolving view of atherosclerosis as a metabolic complication has directed attention towards peroxisome proliferator-activated receptors (PPARs) as transcriptional regulators involved in lipid metabolism, inflammation, and atherosclerosis. PPARs, as ligand-activated transcription factors belonging to the nuclear hormone receptor family, can regulate multiple target genes. Extensive data establish expression of all three PPAR isotypes – PPARα, -γ, and -δ/β – throughout the vasculature and inflammatory cells [8]. The focus here is on PPARα, which has been strongly implicated in beta oxidation of fatty acids as well as lipid metabolism. Not surprisingly given these effects, PPARα is expressed mainly in higher energy-requiring tissues like skeletal muscle and heart as well as the liver. Activation of PPARα has been reported to improve levels of triglycerides, HDL, and the overall atherogenic plasma lipid profile, while also potentially modulating inflammation as well as insulin resistance itself [6], [7]. PPARα has been reported to be activated by natural ligands such as fatty acids and their derivatives, and contain leukotrienes products [9], [10], as well as by drugs such as the lipid-lowering fibrates [11], [12], [13]. Pharmacological treatment of patients with fibrates has been shown to lower cardiovascular mortality although this dataset is mixed as will be discussed further below.
One of the many lines of evidence that suggest PPARα may play a role in atherosclerosis derives from the data implicating this receptor in limiting inflammation. In the absence of PPARα, mice have a prolonged response to inflammatory stimuli [9]. PPARs have also been found to modulate the acute phase response of the liver as well as mechanisms of inflammation in the vasculature [14], [15]. Aortas from PPARα-deficient mice display an exacerbated inflammatory response to stimulation with lipopolysaccharide. In addition, murine endothelial cells (EC) and hepatocytes that lack PPARα have increased levels of inflammatory targets such as vascular cell adhesion molecule-1 (VCAM-1) and serum amyloid A (SAA) [10], [16].
PPARα's seeming placement at the nexus of lipid metabolism, energy balance, and inflammation, makes its potential as a target for limiting atherosclerosis of obvious interest. This review examines the various mechanisms through which PPARα has been implicated in atherosclerosis and explores the potential importance of PPARα in atherosclerosis. Although inflammation is an important part of the immune response and necessary for organismal defense, chronic inflammatory activation may also have deleterious, maladaptive effects, including promotion of atherosclerosis and its complications. Given the evidence for PPARα's involvement in limiting inflammation under basal conditions and inhibiting inflammatory responses after inflammatory stimuli forces, this issue will be a focus of the discussion here.
Section snippets
PPARα in the regulation of inflammation in the liver
The liver is an integral and often overlooked player in atherosclerosis, including systemic effects through hepatic function as the organ seat for the synthesis of lipoprotein particles — important contributors to cardiovascular risk. The liver is also the site of synthesis for other acute phase reactants such as C-reactive protein (CRP), fibrinogen, and serum amyloid A (SAA). Levels of these proteins all reportedly correlate with cardiovascular disease [17], [18]. The acute phase response is a
PPARα and endothelial reactivity
Development of atherosclerotic lesions is often preceded by abnormalities in vascular wall reactivity [29]. In many ways, this alteration in arterial function stems from changes in endothelial cells, highlighting one of many examples that have re-defined the endothelium as a dynamic, biologically-active organ rather than just a passive arterial lining. The importance of the endothelium in vessel reactivity and subsequent abnormalities of arterial responses has fostered the use of the term
PPARα and the arterial adhesion and entry of leukocytes
Early atherogenesis is characterized by the recruitment and subsequent entry of leukocytes to an injured endothelium. This endothelial damage can derive directly from risk factors such as hypertension (shear stress), hyperglycemia, and hypercholesterolemia. Leukocytes are recruited to these sites of injury by following a chemical gradient of released chemoattractant cytokines, or chemokines, released from the activated endothelial cells and the sub-endothelium. Subsequently, these inflammatory
PPARα and local immune cell responses
T lymphocytes and dendritic cells (DCs) are now recognized as important players in atherosclerosis, with the recruitment, activation, and proliferation of these immune cells contributing to lesion formation and its complications. Activated T lymphocytes and dendritic cells (DC), the most potent antigen-presenting cells, co-localize in atheromata [48]. After their recruitment and entry into the vessel wall, T lymphocytes, consisting of mainly CD4-positive cells, differentiate from naive Th0
PPARα, oxidative modification of lipoproteins, and foam cell formation
Elevated LDL-cholesterol is a well-established risk factor for cardiovascular disease (CAD), as evident from the strong association between genetic disorders of cholesterol metabolism characterized by marked elevated LDL levels and premature CAD; patients with familial hypercholesterolemia can have myocardial infartions as early as 1 to 2 years of age. In more common forms of CAD, LDL confers an increased risk of atherosclerosis across a very wide range of LDL levels. Indeed, as clinical trial
PPARα and plaque stability and thrombogenicity
During the progression from early fatty streaks to a more complex atherosclerotic lesion, SMCs proliferate, migrate, and accumulate in the atherosclerotic plaque. The production of extracellular matrix (ECM) components by SMCs can further expand the lesion and foster a more fibrous plaque. The SMC is also the source of the material that makes up the fibrous cap that separates the necrotic, lipid-rich prothrombotic core and the circulation. Rupture of the fibrous cap, which typically occurs in
Connecting lipoprotein metabolism to PPARα activation in vivo: implications for inflammation and atherosclerosis
Although critical early work established that certain fatty acids could activate all PPAR isotypes, until recently little information existed on how metabolism of lipoproteins might be connected to PPAR responses. Given the complexity of lipid metabolism, such pathways might help explain selective PPAR activation or how abnormalities in lipid metabolism might be defined in part by changes in PPAR activation. Interestingly, many aspects of the PPAR field have been defined by responses to
PPARα activation: good or bad?
Although the bulk of PPARα data argues for PPARα as a mechanism for limiting inflammation and atherosclerosis, it is important to note countering evidence that suggests PPARα may also exert untoward effects. Although mouse bone marrow transplantation experiments using PPARα deficient macrophages support PPARα as decreasing atherosclerosis, crossing PPARα deficient mice with ApoE-deficient mice led to more atherosclerosis rather than decreasing atherosclerosis as might have been predicted if
Conclusion
Atherosclerosis is a chronic disease characterized by lipid and fibrous depositions in the arterial wall in the setting of a chronic pro-coagulant, pro-inflammatory state. The potential importance of PPARα in atherosclerosis is evident by its transcriptional regulation of pathways involved in atherogenic dyslipidemia, extracellular matrix remodeling, cholesterol efflux, thrombogenicity, and inflammation. As such, PPARα may well be involved in all the stages of atherosclerosis, from the earliest
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