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Aerobic Exercise Stabilizes HIF1α through P4HA1 to Activate Nrf2/GPX4 Inhibiting Ferroptosis and Attenuating Diabetic
Sicong Xie1, Mingjun Wang2, Chenshuo Yu1
1Department of Rehabilitation Medicine, School of Acupuncture-Moxibustion and Tuina and School of Health Preservation and Rehabilitation, Nanjing University of Chinese Medicine, Nanjing, China.
Background:
Diabetic cardiomyopathy (DCM) is a severe complication of end-stage diabetes characterised by cardiac hypertrophy and heart failure. Previous studies have shown that aerobic exercise enhances the body's antioxidant capacity, protects the heart, and alleviates DCM-mediated heart damage; however, the specific mechanism remains unclear. The aim of this study was to investigate the protective effects and underlying mechanisms of aerobic exercise against DCM.
Methods:
Rat cardiomyocytes (H9C2) were cultivated in vitro and stimulated with high glucose and palmitic acid to assess cell death, mitochondrial activity, oxidative stress indicators, mitochondrial morphology, and ferroptosis-related proteins. A DCM rat model was established to evaluate cardiac function, myocardial enzyme levels and pathology, collagen, and ferroptosis-related proteins in each group. Bioinformatics analysis was used to identify the roles of prolyl 4-hydroxylase subunit alpha 1 (P4HA1) and hypoxia inducible factor 1 subunit alpha (HIF1α) in regulating ferroptosis. Overexpression and knockdown of P4HA1 and HIF1α were used to further validate the relevant mechanisms.
Results:
DCM occurrence and development were closely linked to ferroptosis. Alongside apoptosis and necrosis, ferroptosis is characterised mainly by mitochondrial changes, the appearance of lipid peroxides, and increased reactive oxygen species in myocardial cells or tissues. Expression levels of ferroptosis-related proteins were significantly altered, but improved by aerobic exercise. Using bioinformatics and immunoprecipitation, we found that aerobic exercise reduces HIF1α ubiquitination by activating P4HA1. The HIF1α accumulation activates the nuclear factor erythroid 2-related factor 2 (Nrf2)/glutathione peroxidase 4 (GPX4) signaling pathway, inhibiting ferroptosis.
Conclusion:
In summary, aerobic exercise increases P4HA1 expression and inhibits HIF1α hydroxylation, preventing its ubiquitination and degradation. This consequently activates the Nrf2/GPX4 signaling pathway, further exerting antioxidant effects, attenuating ferroptosis, and ultimately ameliorating DCM.
