HIF-1α ameliorates myocardial apoptosis and promotes angiogenesis in diabetic myocardial infarction.

Diabetic hearts exhibit low hypoxia-inducible factor-1α (HIF-1α) activity, which aggravates cardiomyocyte apoptosis and impairs angiogenesis after infarction. Whether sustained HIF-1α expression can rescue these defects remains unclear. Here, a triple-point mutant that escapes von Hippel-Lindau (VHL)-mediated degradation (HIF-1α-Trip; P402A/P564A/N803A) was delivered to primary cardiomyocytes, cardiac microvascular endothelial cells (CMECs) and to streptozotocin-diabetic mice subjected to permanent left-anterior-descending (LAD) ligation. HIF-1α-Trip restored PI3K/Akt signaling, increased the Bcl-2/Bax ratio, and reduced TUNEL+ cardiomyocytes under high-glucose/hypoxic stress. In vivo, intramyocardial AAV9-HIF-1α-Trip increased CD31-positive microvessel density, improved cardiac function and reduced Masson-defined fibrosis-despite ongoing hyperglycemia. These benefits were recapitulated in high-glucose/hypoxic cardiomyocytes and CMECs, where HIF-1α-Trip decreased cardiomyocyte apoptosis and enhanced CMEC proliferation, migration, and tube formation while up-regulating VEGF secretion. Thus, local delivery of oxidation-resistant HIF-1α mutant simultaneously curbs apoptosis and promotes angiogenesis in diabetic myocardial infarction, offering a straightforward antioxidant gene therapy.