Hypoxia-Inducible Factor 1α Polymorphism and Coronary Collaterals in Patients With Ischemic Heart Disease

Resar, Jon R.; Roguin, Ariel; Voner, Jeffery; Nasir, Khurram; Hennebry, Thomas A.; Miller, Julie M.; Ingersoll, Roxann; Kasch, Laura; Semenza, Gregg L.

doi:10.1378/chest.128.2.787

Cited by 114 publications

(101 citation statements)

References 16 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…A human genetic polymorphism that results in the substitution of serine for proline at residue 582 of HIF-1␣ is associated with type 2 diabetes (29). The P582S polymorphism is also associated with absence of coronary collaterals in patients with ischemic heart disease (30). Taken together with our data, these studies provide a link between HIF-1, diabetes, and impaired vascularization in humans and mice.…”

Section: Discussionsupporting

confidence: 74%

Adenoviral transfer of HIF-1α enhances vascular responses to critical limb ischemia in diabetic mice

Sarkar¹,

Fox-Talbot²,

Steenbergen³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

125

View full text Add to dashboard Cite

Diabetes is a major risk factor for ischemic disease. Treatment options for diabetic patients with peripheral arterial disease when revascularization is not possible are limited, resulting in a high incidence of limb amputation. We evaluated the therapeutic potential of AdCA5, an adenovirus encoding a constitutively active form of HIF-1α, in a diabetic model of critical limb ischemia. Diabetic db / db and nondiabetic db /+ mice were subjected to unilateral femoral artery ligation. Limb perfusion, tissue viability, and motor function were more severely impaired in db / db mice. Intramuscular injection of AdCA5 into the ischemic limb of db / db mice increased the recovery of limb perfusion and function, reduced tissue necrosis, rescued the diabetes-associated impairment of circulating angiogenic cells, enhanced endothelial nitric oxide synthase activation, and increased vessel density and luminal area in the ischemic limb.

show abstract

Section: Discussionsupporting

confidence: 74%

Adenoviral transfer of HIF-1α enhances vascular responses to critical limb ischemia in diabetic mice

Sarkar¹,

Fox-Talbot²,

Steenbergen³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

125

View full text Add to dashboard Cite

show abstract

“…Knockout mice lacking the gene encoding the HIF prolyl hydroxylase PHD2, the enzyme targeting HIF alpha proteins for degradation during normoxia, have elevated levels of HIF-1α, increased number of mature medium-sized vessels, and enlarged capillaries in the subendocardial region [58]. A potential role for HIF-1 in cardiac vessel formation in human hearts is supported by the finding that a HIF-1α polymorphism is associated with reduced coronary artery collateral formation, although the mechanism behind this observation remains to be determined [59].…”

Section: Biological Roles For Hif-1 and Hif-2 In Cardiac Angiogenesismentioning

confidence: 99%

Keeping the engine primed: HIF factors as key regulators of cardiac metabolism and angiogenesis during ischemia

2007

View full text Add to dashboard Cite

Myocardial ischemia, the most common cause of cardiac hypoxia in clinical medicine, occurs when oxygen delivery cannot meet myocardial metabolic requirements in the heart. This deficiency can result from either a reduced supply of oxygen (decreased coronary bloodflow) or an increased myocardial demand for oxygen (increased wall stress or afterload). Patients with stable coronary artery disease as well as patients experiencing acute myocardial infarction can experience episodes of severe ischemia. Although hypoxia is an obligatory component, it is not the sole environmental stress experienced by the ischemic heart. Reperfusion after ischemia is associated with increased oxidative stress as the heart reverts to aerobic respiration and thereby generates toxic levels of reactive oxygen species (ROS). During mild ischemia, mitochondrial function is partially compromised and substrate preferences adapt to sustain adequate ATP generation. With severe ischemia, mitochondrial function is markedly compromised and anaerobic metabolism must provide energy no matter what the cost in generation of toxic ROS adducts. Ischemia produces a variety of environmental stresses that impair cardiovascular function. As a result, multiple signaling pathways are activated in mammalian cells during ischemia/reperfusion injury in an attempt to minimize cellular injury and maintain cardiac output. Amongst the transcriptional regulators activated are members of the hypoxia inducible factor (HIF) transcription factor family. HIF factors regulate a variety of genes that affect a myriad of cellular processes including metabolism, angiogenesis, cell survival, and oxygen delivery, all of which are important in the heart. In this review, we will focus on the metabolic and angiogenic aspects of HIF biology as they relate to the heart during ischemia. We will review the metabolic requirements of the heart under normal as well as hypoxic conditions, the effects of preconditioning and its regulation as it pertains to HIF biology, the apparent roles of HIF-1 and HIF-2 in intermediary metabolism, and translational applications of HIF-1 and HIF-2 biology to cardiac angiogenesis. Increased understanding of the role of HIFs in cardiac ischemia will ultimately influence clinical cardiovascular practice.

show abstract

“…Cycles of hypoxia and reoxygenation also potently increase HIF-1α protein levels and HIF-1 transcriptional activity (18)(19)(20)(21). HIF-1α activation has been demonstrated in human hearts under conditions of myocardial ischemia and infarction (22) and patients with coronary artery disease who carry genetic polymorphisms at the human HIF1A locus are more likely to present to medical attention with stable angina rather than with myocardial infarction (23) and are less likely to have coronary collaterals (24).…”

mentioning

confidence: 99%

Hypoxia-inducible factor 1 transcriptional activity in endothelial cells is required for acute phase cardioprotection induced by ischemic preconditioning

Sarkar¹,

Cai²,

Gupta³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Infarction occurs when myocardial perfusion is interrupted for prolonged periods of time. Short episodes of ischemia and reperfusion protect against tissue injury when the heart is subjected to a subsequent prolonged ischemic episode, a phenomenon known as ischemic preconditioning (IPC). Hypoxia-inducible factor 1 (HIF-1) is a transcription factor that mediates adaptive responses to hypoxia/ischemia and is required for IPC. In this study, we performed a cellular and molecular characterization of the role of HIF-1 in IPC. We analyzed mice with knockout of HIF-1α or HIF-1β in Tie2 + lineage cells, which include bone marrow (BM) and vascular endothelial cells, compared with control littermates. Hearts were subjected to 30 min of ischemia and 120 min of reperfusion, either as ex vivo Langendorff preparations or by in situ occlusion of the left anterior descending artery. The IPC stimulus consisted of two cycles of 5-min ischemia and 5-min reperfusion. Mice lacking HIF-1α or HIF-1β in Tie2 + lineage cells showed complete absence of protection induced by IPC, whereas significant protection was induced by adenosine infusion. Treatment of mice with a HIF-1 inhibitor (digoxin or acriflavine) 4 h before Langendorff perfusion resulted in loss of IPC, as did administration of acriflavine directly into the perfusate immediately before IPC. We conclude that HIF-1 activity in endothelial cells is required for acute IPC. Expression and dimerization of the HIF-1α and HIF-1β subunits is required, suggesting that the heterodimer is functioning as a transcriptional activator, despite the acute nature of the response.T he heart requires a constant supply of O 2 for generation of ATP, 95% of which is derived from oxidative phosphorylation (1). Coronary artery stenosis due to an atherosclerotic plaque results in reduced perfusion and myocardial ischemia, especially under conditions of increased myocardial O 2 demand, as occurs when heart work is increased in response to physical exertion or emotional stress. Plaque rupture is a catastrophic event that results in complete arterial occlusion and, within ∼20

show abstract

Hypoxia-Inducible Factor 1α Polymorphism and Coronary Collaterals in Patients With Ischemic Heart Disease

Cited by 114 publications

References 16 publications

Adenoviral transfer of HIF-1α enhances vascular responses to critical limb ischemia in diabetic mice

Adenoviral transfer of HIF-1α enhances vascular responses to critical limb ischemia in diabetic mice

Keeping the engine primed: HIF factors as key regulators of cardiac metabolism and angiogenesis during ischemia

Hypoxia-inducible factor 1 transcriptional activity in endothelial cells is required for acute phase cardioprotection induced by ischemic preconditioning

Contact Info

Product

Resources

About