Fatty Acids Prevent Hypoxia-Inducible Factor-1α Signaling Through Decreased Succinate in Diabetes
| Autor: | Dodd, MS, Sousa Fialho, MDL, Montes Aparicio, CN, Kerr, M, Timm, KN, Griffin, JL, Luiken, JJFP, Glatz, JFC, Tyler, DJ, Heather, LC |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
diabetes
DMOG dimethyloxalylglycine hypoxia FA fatty acid HIF-1α 1103 Clinical Sciences i.p. intraperitoneal fatty acids HIF hypoxia-inducible factor PRECLINICAL RESEARCH FIH factor inhibiting hypoxia-inducible factor SSO sulfo-N-succinimidyl oleate cardiovascular disease PHD prolyl hydroxylase domain IR insulin resistance/resistant MI myocardial infarction BSA bovine serum albumin 1102 Cardiorespiratory Medicine and Haematology metabolism ANOVA analysis of variance DMF dimethyl fumarate |
| Zdroj: | JACC: Basic to Translational Science |
| ISSN: | 2452-302X |
| Popis: | Visual Abstract Highlights • HIF-1α is activated following myocardial infarction, and is a critical transcription factor promoting survival in hypoxia. • Type 2 diabetes blunts HIF-1α activation in ischemia and downstream adaptation to hypoxia. • This effect is mediated by increased long-chain fatty acids, which prevent HIF-1α activation in hypoxia. • Succinate promotes HIF-1α activation by inhibiting the regulatory HIF hydroxylases. Fatty acids decrease succinate concentrations in hypoxia, by blocking increased glycolysis and malate-aspartate shuttle activity. • Pharmacologically activating HIF-1α or increasing succinate concentrations restores the hypoxic response and improves functional recovery post-ischemia in diabetes. Summary 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. |
| Databáze: | OpenAIRE |
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