The role of hypoxia-inducible factors in cardiovascular diseases
Introduction
Oxygen is an important prerequisite for aerobic respiration, which is essential for cardiovascular systems to maintain cellular homeostasis (Waypa, Smith, & Schumacker, 2016). However, when oxygen supply does not meet cellular energy demand, the body will suffer from hypoxia, and the cells are forced to undergo anaerobic respiration (Sendoel & Hengartner, 2014). Hypoxia leads to cellular dysfunction and even cell death, which is a major cause of cardiovascular diseases (CVDs) including atherosclerosis, pulmonary arterial hypertension (PAH), vascular remodeling, and heart failure (Abe, Semba, & Takeda, 2017; Beaudin, Waltz, Hanly, & Poulin, 2017; Liu et al., 2020). In a hypoxic environment, hypoxia-inducible factor (HIF) is significantly induced and enhanced in cells, which mediates most of the cellular responses to hypoxia at the transcriptional level (Abe et al., 2017; Sousa Fialho, Abd Jamil, Stannard, & Heather, 2019). The activity of HIF-α is regulated at the post-translational level. At normoxic conditions, HIF-α protein is hydroxylated and then degraded by the ubiquitin-proteasome system (Maxwell et al., 1999). In contrast, the HIF-α protein is stabilized in hypoxic cells and translocated into the nucleus to form a heterodimer with the β-subunit (Ham 3rd & Raju, 2017), which then binds to the hypoxia-responsive elements (HRE) and activates the transcription of hypoxia-inducible genes (Hu, Wang, Chodosh, Keith, & Simon, 2003; Schodel et al., 2011).
HIF regulates diverse hypoxia-inducible genes, which are related to angiogenesis, erythropoiesis, and cellular metabolism and inflammation (Melillo et al., 1995; Semenza & Wang, 1992; Tuder, Flook, & Voelkel, 1995; Wheaton & Chandel, 2011). In hypoxic conditions, HIF can initiate adaptive processes to low oxygen availability and mediate protective responses by regulating its downstream targets and relevant signaling pathways in cardiovascular systems (Lee, Ko, Ju, & Eltzschig, 2019; Liu et al., 2020). Therefore, HIF has the potential to become a therapeutic target for the prevention and treatment of CVDs. The objective of this review is to give a systematic summary of HIF functions in CVDs. In addition, the potential clinical therapies involving the modulation of HIF pathways will be discussed.
Section snippets
Hypoxia-inducible factor family
HIFs are a series of members which belong to the basic helix-loop-helix PER-ARNT-SIM (bHLH-PAS) transcription factor superfamily (Fig. 1). HIF-1 is a heterodimeric transcription factor consisting of an oxygen-sensitive subunit HIF-1α (120kD) and a constitutive subunit HIF-1β (91-94kD) (Semenza & Wang, 1992). HIF-1α is an 826-amino acid protein, whereas HIF-1β protein has 789 amino acids. HIF-1β was first found as a dimerization partner for the aryl-hydrocarbon receptor in the presence of aryl
Hypoxia-inducible factors and cardiovascular development
Many studies have reported that during embryonic cardiovascular development, there exist hypoxia regions, in which the expression of hypoxia-related markers and HIFs is activated in spatial- and time-restricted patterns (Fig. 3). For example, pimonidazole, one of the hypoxia-related markers, was discovered in different regions of the embryo at various time points (Varia et al., 1998). In vitro cultured chick embryos at the early stage showed positive pimonidazole at Hamburger and Hamilton
Hypoxia-inducible factors in various cardiovascular cells
In response to various stimuli, distinct cell types of the vascular wall show different regulation of HIFs and their target genes. For example, HIF-1 can activate angiogenic-related genes such as VEGF in ECs, induce contractile-related myosin light chain phosphorylation in vascular smooth muscle cells (VSMCs), and regulate phenotypic marker expression in adventitial cell differentiation. The following subsections focus on the HIFs expression and activity and their up- and down-stream mediators
Effects of hypoxia-inducible factors on cardiovascular diseases
HIFs-mediated signaling pathways are involved in many kinds of cardiovascular diseases as shown in Table 2 and we will discuss them in detail as below.
Author contributions
BY and AQ conceived this work, BY, XW, YS, GX, SJ and AQ wrote and revised the manuscript. LS, XC and XH draw the figures and tables. All authors contributed to the article and approved the submitted version.
Funding sources
This work was supported by National Key Research and Development Program of China (2021YFA0805100), National Natural Science Foundation of China (81870186; 82070474), the Importation and Development of High-Caliber Talents Project of Beijing Municipal Institutions (CIT&TCD201904090; CIT&TCD20190332), and The Key Science and Technology Project of Beijing Municipal Institutions (KZ201910025027; KZ202010025032).
Declaration of Competing Interest
The authors declare that there is no conflict of interest.
References (215)
- et al.
HIF-1alpha is essential for myeloid cell-mediated inflammation
Cell
(2003) - et al.
Hypoxia enhances lipid uptake in macrophages: role of the scavenger receptors Lox1, SRA, and CD36
Atherosclerosis
(2013) - et al.
Differential but complementary HIF1alpha and HIF2alpha transcriptional regulation
Molecular Therapy
(2018) - et al.
Epidemiology of peripheral arterial disease and critical limb ischemia
Techniques in Vascular and Interventional Radiology
(2016) - et al.
Attenuating myocardial ischemia by targeting A2B adenosine receptors
Trends in Molecular Medicine
(2013) - et al.
Endogenous adenosine produced during hypoxia attenuates neutrophil accumulation: coordination by extracellular nucleotide metabolism
Blood
(2004) - et al.
Hypoxia inducible-factor1alpha regulates the metabolic shift of pulmonary hypertensive endothelial cells
The American Journal of Pathology
(2010) - et al.
Endothelial to mesenchymal transition contributes to endothelial dysfunction in pulmonary arterial hypertension
The American Journal of Pathology
(2015) - et al.
Heme changes HIF-alpha, eNOS and nitrite production in HUVECs after simvastatin, HU, and ascorbic acid therapies
Microvascular Research
(2016) - et al.
Mitochondrial complex III is required for hypoxia-induced ROS production and cellular oxygen sensing
Cell Metabolism
(2005)
Mitochondrial function in hypoxic ischemic injury and influence of aging
Progress in Neurobiology
Increased endogenous angiogenic response and hypoxia-inducible factor-1alpha in human critical limb ischemia
Journal of Vascular Surgery
Hypoxia inducible factor as a therapeutic target for atherosclerosis
Pharmacology & Therapeutics
Dimerization, DNA binding, and transactivation properties of hypoxia-inducible factor 1
The Journal of Biological Chemistry
Inactivation of maternal Hif-1alpha at mid-pregnancy causes placental defects and deficits in oxygen delivery to the fetal organs under hypoxic stress
Developmental Biology
Hypoxia-inducible factor 1-alpha reduces infarction and attenuates progression of cardiac dysfunction after myocardial infarction in the mouse
Journal of the American College of Cardiology
The role of MicroRNA-21 in venous neointimal hyperplasia: implications for targeting miR-21 for VNH treatment
Molecular Therapy
HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia
Cell Metabolism
The roles of hypoxia signaling in the pathogenesis of cardiovascular diseases
Journal of Atherosclerosis and Thrombosis
Digoxin inhibits development of hypoxic pulmonary hypertension in mice
Proceedings of the National Academy of Sciences of the United States of America
Endothelial hypoxia-inducible factor-1alpha promotes atherosclerosis and monocyte recruitment by upregulating MicroRNA-19a
Hypertension
Investigating mitochondrial metabolism in contracting HL-1 cardiomyocytes following hypoxia and pharmacological HIF activation identifies HIF-dependent and independent mechanisms of regulation
Journal of Cardiovascular Pharmacology and Therapeutics
The terminal portion of the pulmonary arterial tree in people native to high altitudes
Circulation
Regulation of hypoxia-induced pulmonary hypertension by vascular smooth muscle hypoxia-inducible factor-1alpha
American Journal of Respiratory and Critical Care Medicine
Hypoxia Triggers Osteochondrogenic Differentiation of Vascular Smooth Muscle Cells in an HIF-1 (Hypoxia-Inducible Factor 1)-Dependent and Reactive Oxygen Species-Dependent Manner
Arteriosclerosis, Thrombosis, and Vascular Biology
Chronic inhibition of hypoxia-inducible factor prolyl 4-hydroxylase improves ventricular performance, remodeling, and vascularity after myocardial infarction in the rat
Journal of Cardiovascular Pharmacology
Loss of smooth muscle cell hypoxia inducible factor-1alpha underlies increased vascular contractility in pulmonary hypertension
The FASEB Journal
Neuronal HIF-1alpha and HIF-2alpha deficiency improves neuronal survival and sensorimotor function in the early acute phase after ischemic stroke
Journal of Cerebral Blood Flow and Metabolism
Impact of obstructive sleep apnoea and intermittent hypoxia on cardiovascular and cerebrovascular regulation
Experimental Physiology
Conditional HIF-1alpha expression produces a reversible cardiomyopathy
PLoS One
Hypoxia-inducible factor-dependent induction of myeloid-derived netrin-1 attenuates natural killer cell infiltration during endotoxin-induced lung injury
The FASEB Journal
Metabolic remodelling in heart failure
Nature Reviews. Cardiology
Medial hypoxia and adventitial vasa vasorum remodeling in human ascending aortic aneurysm
Front Cardiovasc Med
HIF-1alpha is required for development of the sympathetic nervous system
Proceedings of the National Academy of Sciences of the United States of America
Effects of aging and hypoxia-inducible factor-1 activity on angiogenic cell mobilization and recovery of perfusion after limb ischemia
Circulation Research
Heterozygous deficiency of hypoxia-inducible factor-2alpha protects mice against pulmonary hypertension and right ventricular dysfunction during prolonged hypoxia
The Journal of Clinical Investigation
Mechanisms of angiogenesis and arteriogenesis
Nature Medicine
Angiogenesis in health and disease
Nature Medicine
Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1
Nature Medicine
Adverse effects of Hif1a mutation and maternal diabetes on the offspring heart
Cardiovascular Diabetology
Deficiency of HIF1alpha in antigen-presenting cells aggravates atherosclerosis and type 1 T-helper cell responses in mice
Arteriosclerosis, Thrombosis, and Vascular Biology
Hypoxia at the site of abdominal aortic aneurysm rupture is not associated with increased lactate
Annals of the New York Academy of Sciences
Netrin-1: Focus on its role in cardiovascular physiology and atherosclerosis
JRSM Cardiovascular Disease
Cardia bifida, defective heart development and abnormal neural crest migration in embryos lacking hypoxia-inducible factor-1alpha
Cardiovascular Research
HIF2alpha-arginase axis is essential for the development of pulmonary hypertension
Proceedings of the National Academy of Sciences of the United States of America
Cardiovascular adaptation to hypoxia and the role of peripheral resistance
Elife
Late neuroprogenitors contribute to normal retinal vascular development in a Hif2a-dependent manner
Development
Prolyl-4 hydroxylase 2 (PHD2) deficiency in endothelial cells and hematopoietic cells Induces obliterative vascular remodeling and severe pulmonary arterial hypertension in mice and humans through hypoxia-inducible factor-2alpha
Circulation
Therapeutic targeting of vascular remodeling and right heart failure in pulmonary arterial hypertension with a HIF-2alpha inhibitor
American Journal of Respiratory and Critical Care Medicine
Expression of constitutively stable hybrid hypoxia-inducible factor-1alpha protects cultured rat cardiomyocytes against simulated ischemia-reperfusion injury
American Journal of Physiology. Cell Physiology
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