HIF‐2: The Missing Link Between Obesity and Cardiomyopathy

Introduction to HIF Pathway T he evolutionarily conserved hypoxia-inducible factor (HIF) pathway is present ubiquitously in mammalian cells and plays a critical role in the regulation of energy metabolism, especially glucose utilization. HIF is a transcription factor consisting of an O2-sensitive HIF-a (HIF-1a or HIF-2a) and the O2-insensitive HIF-1b subunit. 2 Under most physiologically normoxic conditions (>3% O2), HIF-a is hydroxylated by prolyl hydroxylases (PHD) at 2 proline residues located in the oxygen-dependent degradation domain (ODD), which leads to interaction with the von Hippel Lindau protein pVHL and subsequent degradation by proteasomes. When tissue oxygenation decreases to, for example, <2% O2, HIF-a hydroxylation diminishes and becomes stabilized. While the PHDs themselves can act as oxygen sensors, the mitochondria has also been proposed as a critical organelle responsible for cellular oxygen sensing, presumably through complex III. Mitochondrial oxygen sensing may be more critical for acute, rapid physiological changes that are needed to respond to hypoxic conditions. In contrast to hypoxia, under aerobic conditions additional mechanisms have been proposed for increased HIF-a. In particular, growth factor receptor tyrosine kinase and protooncogene-mediated pathways can also augment HIF-a expression through translational regulation. Thus, depending on the tissue microenvironment, different mechanisms can be used to increase HIF-a levels and transcriptional activity. Obesity and the Tissue Microenvironment