Activation of HIF1α Rescues the Hypoxic Response and Reverses Metabolic Dysfunction in the Diabetic Heart

• Published in: Diabetes (New York, N.Y.) Vol. 70; no. 11; pp. 2518 - 2531
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States American Diabetes Association 01-11-2021
• Subjects: Adaptation, Physiological; Anemia, Sickle Cell; Animals; Cardiomyocytes; Cell Line; Clinical trials; Diabetes; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies - metabolism; Energy Metabolism; Gene Expression Regulation - drug effects; Gene Expression Regulation - physiology; Glucose metabolism; Heart; Heart diseases; Humans; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit - genetics; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Hypoxia-inducible factors; Insulin; Insulin Resistance; Ischemia; Kidney diseases; Metabolism; Mitochondria; Muscle contraction; Myocardial infarction; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - physiology; Oxidation; Oxygen - metabolism; Oxygen - pharmacology; Phenotypes; Pluripotent Stem Cells - drug effects; Pluripotent Stem Cells - metabolism; Pyrazoles - pharmacology; Rats; Transcription activation; Triazoles - pharmacology
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/DB21-0398

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.