Activation of HIF1α Rescues the Hypoxic Response and Reverses Metabolic Dysfunction in the Diabetic Heart
| Autor: | Lisa C. Heather, Damian J. Tyler, Maria da Luz Sousa Fialho, Claudia N. Montes Aparicio, Kaitlyn M.J.H. Dennis, Marcos Castro-Guarda, Emmanuelle Massouridès, Ujang Purnama, Carolyn A. Carr |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Cardiac function curve
Pluripotent Stem Cells medicine.medical_specialty Diabetic Cardiomyopathies Endocrinology Diabetes and Metabolism Type 2 diabetes Anemia Sickle Cell Carbohydrate metabolism Cell Line Diabetes Mellitus Experimental Insulin resistance Internal medicine Internal Medicine medicine Animals Humans Myocytes Cardiac Myocardial infarction Transcription factor Beta oxidation business.industry Hypoxia (medical) Triazoles medicine.disease Hypoxia-Inducible Factor 1 alpha Subunit Adaptation Physiological Rats Oxygen Endocrinology Metabolism Diabetes Mellitus Type 2 Gene Expression Regulation Pyrazoles medicine.symptom Insulin Resistance business Energy Metabolism |
| Zdroj: | Diabetes |
| ISSN: | 1939-327X |
| Popis: | 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-ischaemic remodelling observed following myocardial infarction in T2D. Molidustat is a HIF stabiliser currently undergoing clinical trials for the treatment of renal anaemia associated with chronic kidney disease, however, it may provide a route to pharmacologically activate HIF1α in the T2D heart. In human cardiomyocytes, molidustat stabilised HIF1α and downstream HIF target genes, promoting anaerobic glucose metabolism. In hypoxia, insulin resistance blunted HIF1α activation and downstream signalling, 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, whilst 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 stabilisation can overcome the blunted hypoxic response induced by insulin resistance. In vivo this corrected the abnormal metabolic phenotype and impaired post-ischaemic 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|