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

ABSTRACT: Hypoxia-inducible factor (HIF)-1? is essential following a myocardial infarction (MI), and diabetic patients have poorer prognosis post-MI. Could HIF-1? activation be abnormal in the diabetic heart, and could metabolism be causing this? Diabetic hearts had decreased HIF-1? protein following ischemia, and insulin-resistant cardiomyocytes had decreased HIF-1?-mediated signaling and adaptation to hypoxia. This was due to elevated fatty acid (FA) metabolism preventing HIF-1? protein stabilization. FAs exerted their effect by decreasing succinate concentrations, a HIF-1? activator that inhibits the regulatory HIF hydroxylase enzymes. In vivo and in vitro pharmacological HIF hydroxylase inhibition restored HIF-1? accumulation and improved post-ischemic functional recovery in diabetes.

SUBMITTER: Dodd MS 

PROVIDER: S-EPMC6115650 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature