Hypoxia-inducible factor 1 and cardiovascular disease

Abstract

Cardiac function is required for blood circulation and systemic oxygen delivery. However, the heart has intrinsic oxygen demands that must be met to maintain effective contractility. Hypoxia-inducible factor 1 (HIF-1) is a transcription factor that functions as a master regulator of oxygen homeostasis in all metazoan species. HIF-1 controls oxygen delivery, by regulating angiogenesis and vascular remodeling, and oxygen utilization, by regulating glucose metabolism and redox homeostasis. Analysis of animal models suggests that by activation of these homeostatic mechanisms, HIF-1 plays a critical protective role in the pathophysiology of ischemic heart disease and pressure-overload heart failure.

Figure 1

HIF-1 mediates cell type–specific responses to hypoxia. The relative expression levels of mRNAs encoding vascular endothelial growth factor (VEGF), placental growth factor (PGF), platelet-derived growth factor B (PDGFB), angiopoietin 1 (ANGPT1), and ANGPT2 were determined in primary cultures of cardiac fibroblasts (CF), cardiomyocytes (CM), vascular smooth muscle cells (SM), and vascular endothelial cells (EC) exposed for 24 h either to (a) 1% versus 20% O₂ or to (b) an adenoviral vector encoding a constitutively active form of HIF-1α(AdCA5) versus Escherichia coli β-galactosidase (AdLacZ) at 20% O₂. Red, yellow, and green squares indicate values for the indicated ratios (1% O₂:20% O₂ and AdCA5:AdLacZ) of >1, = 1, and < 1, respectively. HIF-1 target gene products are depicted as blue rectangles. Adapted from Reference .

Figure 2

HIF-1 coordinately regulates vascular responses to hypoxia and ischemia. HIF-1 activates the transcription of multiple genes encoding angiogenic growth factors and cytokines (blue rectangles), which bind to cognate cell surface receptors (red rectangles) to mediate their biological effects on endothelial cells (ECs), vascular smooth muscle cells (SMCs), endothelial progenitor cells (EPCs), mesenchymal stem cells (MSCs), and other bone marrow–derived angiogenic cells (BMDACs). The blue outlines denote receptors whose expression is also regulated by HIF-1 in certain cell types.

Figure 3

Remodeling of a collateral blood vessel in response to coronary artery stenosis. (a) Two major coronary arteries, which are connected by an undeveloped collateral vessel, are shown. (b) Atherosclerotic plaque formation (tan oval ) results in stenosis of one artery. (c) Plaque rupture results in complete arterial obstruction (brown oval ), leading to a large myocardial infarction (MI). (d ) Remodeling of the collateral vessel to increase luminal diameter results in increased blood flow. (e) When plaque rupture occurs, the reduction in blood flow is mitigated, resulting in a smaller area of infarction. Black arrows denote the direction and relative magnitude of blood flow.

Figure 4

Adenosine production mediated by HIF-1 contributes to the cardioprotective effect of ischemic preconditioning. A_2BAR denotes the adenosine A_2B receptor.

Figure 5

Metabolic adaptations that are mediated by HIF-1 and that may contribute to the cardioprotective effect of ischemic preconditioning. HIF-1 activates the transcription of genes whose protein products (LDHA, PDK1, PDK3, COX4I2, LON, BNIP3, BNIP3L, and miR210) play key roles in reducing mitochondrial oxidative metabolism and thereby in reducing the generation of reactive oxygen species (ROS). However, it is not known whether HIF-1 activates any of these genes in the heart in response to ischemic preconditioning.