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

Abstract

Type 2 diabetes (T2D) impairs hypoxia-inducible factor (HIF)1a activation, a master transcription factor that drives cellular adaptation to hypoxia. Reduced activation of HIF1a 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 pro-vide a route to pharmacologically activate HIF1a in the T2D heart. In human cardiomyocytes, molidustat stabi-lized HIF1a and downstream HIF target genes, promoting anaerobic glucose metabolism. In hypoxia, insulin resistance blunted HIF1a 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 conclu-sion, pharmacological HIF1a stabilization can over-come 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 trans-latability of HIF1a activation in the diabetic heart.