HIF in the heart: development, metabolism, ischemia, and atherosclerosis

Abstract

The heart forms early in development and delivers oxygenated blood to the rest of the embryo. After birth, the heart requires kilograms of ATP each day to support contractility for the circulation. Cardiac metabolism is omnivorous, utilizing multiple substrates and metabolic pathways to produce this energy. Cardiac development, metabolic tuning, and the response to ischemia are all regulated in part by the hypoxia-inducible factors (HIFs), central components of essential signaling pathways that respond to hypoxia. Here we review the actions of HIF1, HIF2, and HIF3 in the heart, from their roles in development and metabolism to their activity in regeneration and preconditioning strategies. We also discuss recent work on the role of HIFs in atherosclerosis, the precipitating cause of myocardial ischemia and the leading cause of death in the developed world.

Figure 1. HIF1 expression and function in the developing mouse heart.

(A) Mouse heart development occurs over a period of 7 days, beginning with formation of the cardiac crescent, followed by looping, chamber formation and trabeculation, and finally septation. HIF1α stabilization has been detected at E9.5 in the nascent chambers and outflow track and then becomes restricted to the compact myocardium at E12.5. By E14.5, HIF1α is restricted to the interventricular septum (IVS). (B) Possible targets and functions of HIF1 during heart embryogenesis. HIF1 is thought to promote cardiomyocyte proliferation, glycolysis, and cardiomyocyte specification in embryonic cardiomyocytes. A switch from glycolysis to oxidative phosphorylation is dependent on HIF1α compartmentalization in different regions of the heart over time. LV, left ventricle; RV, right ventricle.

Figure 2. Effects of HIF on metabolism.

HIF expression or stabilization has many effects on cell metabolism, both directly and indirectly. Under normoxic conditions, HIF1α and HIF2α (HIFα) are hydroxylated by PHDs (and FIH) using available oxygen and α-ketoglutarate, which leads to proteosomal degradation. When oxygen tension is low, HIFα translocates to the nucleus, where it binds to DNA with its heterodimeric binding partner HIFβ to initiate transcription of HIF target genes. These transcription products affect all levels of cellular metabolism to reduce oxidative phosphorylation (OXPHOS) in mitochondria and favor glycolysis, from substrate transport to apoptotic signaling molecules (e.g., BNIP3). Some evidence suggests that HIFα may also directly modulate mitochondrial metabolism, through a currently undefined mechanism. Metabolite levels are independently affected by changes in oxygen tension and HIF expression through reduction of PHD activity, which influences concentrations of several citric acid metabolites (e.g., α-ketoglutarate and succinate). Dashed lines indicate transport across the mitochondrial membrane, where these metabolites serve distinct roles in each location. PPP, pentose phosphate pathway.

Figure 3. HIF1α plays multiple roles in the development of atherosclerosis.

This sketch shows the major effects of HIF1α on the three most important cell types in atherosclerosis: endothelial cells, macrophages, and smooth muscle cells. Whereas HIF1α directly induces vascular endothelial growth factor (VEGF), endothelin-1, and matrix metalloproteinases (MMPs) in endothelial cells to facilitate angiogenesis, its effect on vascular smooth muscle cells is to induce proliferation of these cells in the atheroma by upregulating factors such as CD98 and macrophage migration inhibitory factor (MIF). HIF1α also regulates lesional macrophage foam cell function by rendering the cells more inflammatory and apoptotic while suppressing their capacity to metabolize lipids.