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Activation of HIF1α Rescues the Hypoxic Response and Reverses Metabolic Dysfunction in the Diabetic Heart.
Sousa Fialho, Maria da Luz; Purnama, Ujang; Dennis, Kaitlyn M J H; Montes Aparicio, Claudia N; Castro-Guarda, Marcos; Massourides, Emmanuelle; Tyler, Damian J; Carr, Carolyn A; Heather, Lisa C.
Afiliación
  • Sousa Fialho MDL; Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, U.K.
  • Purnama U; Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, U.K.
  • Dennis KMJH; Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, U.K.
  • Montes Aparicio CN; Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, U.K.
  • Castro-Guarda M; Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, U.K.
  • Massourides E; Centre d'Etude des Cellules Souches/I-Stem, INSERM UMR 861, AFM-Téléthon, Corbeil-Essonnes, France.
  • Tyler DJ; Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, U.K.
  • Carr CA; Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, U.K.
  • Heather LC; Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, U.K. lisa.heather@dpag.ox.ac.uk.
Diabetes ; 70(11): 2518-2531, 2021 11.
Article en En | MEDLINE | ID: mdl-34526367
Type 2 diabetes (T2D) impairs hypoxia-inducible factor (HIF)1α activation, a master transcription factor that drives cellular adaptation to hypoxia. Reduced activation of HIF1α contributes to the impaired post-ischemic remodeling observed following myocardial infarction in T2D. Molidustat is an HIF stabilizer currently undergoing clinical trials for the treatment of renal anemia associated with chronic kidney disease; however, it may provide a route to pharmacologically activate HIF1α in the T2D heart. In human cardiomyocytes, molidustat stabilized HIF1α and downstream HIF target genes, promoting anaerobic glucose metabolism. In hypoxia, insulin resistance blunted HIF1α activation and downstream signaling, but this was reversed by molidustat. In T2D rats, oral treatment with molidustat rescued the cardiac metabolic dysfunction caused by T2D, promoting glucose metabolism and mitochondrial function, while suppressing fatty acid oxidation and lipid accumulation. This resulted in beneficial effects on post-ischemic cardiac function, with the impaired contractile recovery in T2D heart reversed by molidustat treatment. In conclusion, pharmacological HIF1α stabilization can overcome the blunted hypoxic response induced by insulin resistance. In vivo this corrected the abnormal metabolic phenotype and impaired post-ischemic recovery of the diabetic heart. Therefore, molidustat may be an effective compound to further explore the clinical translatability of HIF1α activation in the diabetic heart.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Pirazoles / Triazoles / Subunidad alfa del Factor 1 Inducible por Hipoxia / Cardiomiopatías Diabéticas Límite: Animals / Humans Idioma: En Revista: Diabetes Año: 2021 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Pirazoles / Triazoles / Subunidad alfa del Factor 1 Inducible por Hipoxia / Cardiomiopatías Diabéticas Límite: Animals / Humans Idioma: En Revista: Diabetes Año: 2021 Tipo del documento: Article Pais de publicación: Estados Unidos