Hypoxia-inducible factor (HIF)-1α is essential following a myocardial infarction (MI), and diabetic patients have poorer prognosis post-MI. Could HIF-1α activation be abnormal in the diabetic heart, and could metabolism be causing this? Diabetic hearts had decreased HIF-1α protein following ischemia, and insulin-resistant cardiomyocytes had decreased HIF-1α-mediated signaling and adaptation to hypoxia. This was due to elevated fatty acid (FA) metabolism preventing HIF-1α protein stabilization. FAs exerted their effect by decreasing succinate concentrations, a HIF-1α activator that inhibits the regulatory HIF hydroxylase enzymes. In vivo and in vitro pharmacological HIF hydroxylase inhibition restored HIF-1α accumulation and improved post-ischemic functional recovery in diabetes.
JACC Basic Transl Sci
485 - 498
ANOVA, analysis of variance, BSA, bovine serum albumin, DMF, dimethyl fumarate, DMOG, dimethyloxalylglycine, FA, fatty acid, FIH, factor inhibiting hypoxia-inducible factor, HIF, hypoxia-inducible factor, HIF-1α, IR, insulin resistance/resistant, MI, myocardial infarction, PHD, prolyl hydroxylase domain, SSO, sulfo-N-succinimidyl oleate, cardiovascular disease, diabetes, fatty acids, hypoxia, i.p., intraperitoneal, metabolism