Abstract
Background:
Diabetes mellitus (DM), characterized by hyperglycemia, is intricately linked with cardiovascular complications. Hyperglycemia induces oxidative stress, compromising mitochondria energy metabolism disturbances, leading to cardiomyocyte hypoxia and dysregulation of hypoxia-inducible factor-1α (HIF-1α), thereby exacerbating diabetic myocardial injury. Roxadustat (FG-4592), as an inhibitor of HIF-PHD, reduces HIF-1α degradation and regulates the transcription and function of downstream target genes. This study explores the protective effect of FG-4592 on the diabetic myocardium and further investigates the specific mechanisms responsible for this action.
Methods:
We established diabetic myocardial injury mice and high glucose-induced rat cardiomyocyte models, administered FG-4592 pretreatment to clarify the protective effects and related mechanisms of FG-4592 on diabetic myocardial injury by detecting changes in oxidative stress, mitochondrial function, and related pathways.
Results:
FG-4592 demonstrated cardioprotective effects in diabetic mice by regulating mitochondrial structure and function, as well as maintaining oxidative stress balance in the myocardium. It stabilized HIF-1α, activated UCP2, and enhanced the PI3K/AKT/Nrf2 pathway, reducing mitochondrial superoxide production, improving mitochondrial respiratory potential, and modulating oxidative stress markers in high glucose-induced cardiomyocytes.
Conclusions:
FG-4592 exerts protective effects against diabetic myocardial injury by reducing oxidative stress. The mechanism is linked with the upregulation of HIF-1α and UCP2, which subsequently activate the PI3K/AKT/Nrf2 signaling pathway.
Keywords:
Diabetes mellitus; Diabetic myocardial injury; Hypoxia-inducible factor -1α; Oxidative stress; Roxadustat; Uncoupling protein 2.