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.
Keywords: 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.