Hypoxia-inducible factors in physiology and medicine

Abstract

Oxygen homeostasis represents an organizing principle for understanding metazoan evolution, development, physiology, and pathobiology. The hypoxia-inducible factors (HIFs) are transcriptional activators that function as master regulators of oxygen homeostasis in all metazoan species. Rapid progress is being made in elucidating homeostatic roles of HIFs in many physiological systems, determining pathological consequences of HIF dysregulation in chronic diseases, and investigating potential targeting of HIFs for therapeutic purposes.

Figure 1. Regulation of Glucose Metabolism

Under hypoxic conditions, HIF-1 activates the transcription of genes encoding: glucose transporters and glycolytic enzymes, which increase flux of glucose to pyruvate; PDK1 (encoding pyruvate dehydrogenase kinase), which inactivates PDH (pyruvate dehydrogenase), the mitochondrial enzyme that converts pyruvate to acetyl CoA for entry into the tricarboxylic acid (TCA/citric acid/Krebs) cycle; LDHA, which converts pyruvate to lactate; and BNIP3 and BNIP3L, which induce mitochondrial autophagy. The shunting of substrate away from the mitochondria reduces ATP production but prevents excess ROS production that occurs due to inefficient electron transport under hypoxic conditions.

Figure 2. Vascular Effects of Continuous and Intermittent Hypoxia

(A) Prolonged continuous alveolar hypoxia results in pulmonary arterial hypertension due to the activation of both HIF-1α and HIF-2α, leading to changes in pulmonary arterioles that reduce luminal diameter, thereby increasing pulmonary vascular resistance. (B) Chronic intermittent hypoxia results in systemic arterial hypertension due to activation of HIF-1α and degradation of HIF-2α. Increased HIF-1α-dependent expression of NADPH oxidase 2 (NOX2), which generates superoxide anion, and decreased HIF-2α-dependent expression of superoxide dismutase 2 (SOD2), which consumes superoxide, result in increased ROS levels in the carotid body, leading to sympathetic nervous system activation and systemic hypertension.