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