HIF in the heart: development, metabolism, ischemia, and atherosclerosis
Andrew Kekūpaʻa Knutson, Allison L Williams, William A. Boisvert, Ralph V. Shohet
Abstract
Hypoxia-inducible factor 1 (HIF1) is the central actor of an ancient, highly conserved pathway that responds to low-oxygen conditions. This transcription factor is composed of two subunits: constitutively expressed HIF1 and oxygen-sensitive HIF1 (1). In normoxic conditions, the HIF prolyl hydroxylases (PHDs) and asparaginyl hydroxylase (Factor Inhibiting HIF or FIH, respectively) modify residues on HIF1 that target the protein for degradation and prevent its transcriptional activity (2, 3). During hypoxia, these posttranslational modifications are limited, allowing HIF1 to enter the nucleus, dimerize with HIF1, and bind to genomic hypoxia response elements to promote transcription. Another HIF isoform, HIF2, senses oxygen and plays a more restricted, albeit important role, especially in the vasculature (4). Less is known about the final member, HIF3; analysis of this isoform has been complicated by multiple variants encoded from the Hif3a locus (i.e., NEPAS and IPAS). Additionally, full-length HIF3 lacks a C-terminal transactivation domain but still dimerizes with HIF1, thereby acting as a negative regulator of HIF1 and HIF2 activity (5).