Cardiac myocyte‐specific HIF‐1α deletion alters vascularization, energy availability, calcium flux, and contractility in the normoxic heart

Abstract

At a resting pulse rate the heart consumes almost twice-as much oxygen per gram tissue as the brain and more than 43 times more than resting skeletal muscle (1). Unlike skeletal muscle, cardiac muscle cannot sustain anaerobic metabolism. Balancing oxygen demand with availability is crucial to cardiac function and survival, and regulated gene expression is a critical element of maintaining this balance. We investigated the role of the hypoxia-inducible transcription factor HIF-1alpha in maintaining this balance under normoxic conditions. Cardiac myocyte-specific HIF-1alpha gene deletion in the hearts of genetically engineered mice caused reductions in contractility, vascularization, high-energy phosphate content, and lactate production. This was accompanied by altered calcium flux and altered expression of genes involved in calcium handling, angiogenesis, and glucose metabolism. These findings support a central role for HIF-1alpha in coordinating energy availability and utilization in the heart and have implications for disease states in which cardiac oxygen delivery is impaired. Heart muscle requires a constant supply of oxygen. When oxygen supply does not match myocardial demand cardiac contractile dysfunction occurs, and prolongation of this mismatch leads to apoptosis and necrosis. Coordination of oxygen supply and myocardial demand involves immediate adaptations, such as coronary vasodilatation, and longer-term adaptations that include altered patterns of gene expression (2-4). How the expression of multiple genes is coordinated with oxygen availability in the heart and the impact of oxygen-dependent gene expression on cardiac function are insufficiently understood. Further elucidating these relationships may help clarify the molecular pathology of various cardiovascular disease states, including ischemic cardiomyopathy and myocardial hibernation (5, 6).

Hypoxia inducible factor 1α regulates T cell receptor signal transduction

“…Our results showing that constitutive stabilization of Hif-1␣ leads to overexpression of the Serca2 pump and a phenotype of diminished Ca 2ϩ signaling in thymocytes are consistent with previously reported findings demonstrating that targeted cardiomyocyte deficiency in Hif-1␣ causes diminished expression of hypoxia response genes, prolonged Ca 2ϩ signaling, and impaired cardiac contractility (33). Most importantly, expression of Serca2 was diminished in Hif-1␣ Ϫ/Ϫ cardiomyocytes, suggesting that Serca2 is regulated directly or indirectly by Hif-1␣.…”

Hypoxia Increases Sirtuin 1 Expression in a Hypoxia-inducible Factor-dependent Manner

“…Sirt1 and HIF are critical regulators of physiological processes in mammals, including several affected by hypoxia or ischemia (46), such as metabolic adaptation (47)(48)(49), angiogenesis (50 -55), and oxidative stress defense mechanisms (56). A logical expectation is that feedback mechanisms may exist for transcription factors whose target genes encode genetic regulators, which in turn act upon the transcription factor itself.…”

Cobalt promotes angiogenesis via hypoxia-inducible factor and protects tubulointerstitium in the remnant kidney model

“…The number of vessels in cobalt-treated kidneys that expressed a-SMA was comparable to those in the vehicle-treated kidneys (not shown), consistent with a previous report concerning the heart. 38 It is important to note that the new vessels did not show any evidence of vascular leakage. Evans blue content in the remnant kidney revealed no difference between vehicle-and Co-treated RK groups, nor was there any significant difference observed when kidneys were subjected to ischemia-reperfusion injury, a disease model characterized by interstitial edema in its early stage (not shown).…”