Fatty Acids Prevent Hypoxia-Inducible Factor-1α Signaling Through Decreased Succinate in Diabetes.

Abstract

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.

• Authors: Michael S Dodd, Maria da Luz Sousa Fialho, Claudia N Montes Aparicio, Matthew Kerr, Kerstin N Timm, Julian L Griffin, Joost J F P Luiken, Jan F C Glatz, Damian J Tyler, Lisa C Heather
• Journal: JACC. Basic to translational science (JACC Basic Transl Sci) Vol. 3 Issue 4 Pg. 485-498 (Aug 2018) ISSN: 2452-302X [Electronic] United States
• PMID: 30175272 (Publication Type: Journal Article)