Fatty Acids Prevent Hypoxia-InducibleFactor-1aSignaling Through DecreasedSuccinate in Diabetes

M. S. Dodd, Maria da Luz Sousa Fialho, Claudia N. Montes Aparicio, Matthew Kerr, K. N. Timm, J.L. Griffin, Joannes Luiken, Jan Glatz, Damian J. Tyler, Lisa C. Heather*

*Corresponding author for this work

    Research output: Contribution to journalArticleAcademicpeer-review

    Abstract

    SUMMARYHypoxia-inducible factor (HIF)-1ais essential following a myocardial infarction (MI), and diabetic patients havepoorer prognosis post-MI. Could HIF-1aactivation be abnormal in the diabetic heart, and could metabolism becausing this? Diabetic hearts had decreased HIF-1aprotein following ischemia, and insulin-resistant cardio-myocytes had decreased HIF-1a-mediated signaling and adaptation to hypoxia. This was due to elevated fattyacid (FA) metabolism preventing HIF-1aprotein stabilization. FAs exerted their effect by decreasing succinateconcentrations, a HIF-1aactivator that inhibits the regulatory HIF hydroxylase enzymes. In vivo and in vitropharmacological HIF hydroxylase inhibition restored HIF-1aaccumulation and improved post-ischemic func-tional recovery in diabetes.
    Original languageEnglish
    Pages (from-to)485-498
    JournalJACC: Basic to Translational Science
    Volume3
    Issue number4
    DOIs
    Publication statusPublished - 2018

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