Vaspin inhibits ferroptosis: A new hope for treating myocardial ischemia-reperfusion injury.

Objective: Myocardial ischemia-reperfusion injury (MIRI) is a critical pathological basis for cardiovascular diseases. In recent years, the effect of ferroptosis on MIRI has attracted extensive attention. Vaspin, an adipose tissue-derived serine protease inhibitor, has multiple biological functions, including anti-inflammatory and antioxidant effects. This study aims to investigate the molecular mechanism by which vaspin alleviates MIRI by regulating hypoxia-inducible factor-1α (HIF-1α) and ferroptosis signaling pathways.

Material and methods: A mouse model of myocardial ischemia/reperfusion (I/R) and a hypoxia/reoxygenation (H/R) model was used to evaluate the protective effects of vaspin on MIRI. The mechanism by which ferroptosis is modulated by the vaspin/HIF-1α signaling pathway was investigated by constructing a vaspin overexpression adenoviral vector. Myocardial infarct size and histological changes were assessed using triphenyltetrazolium chloride and hematoxylin-eosin staining. Ferroptosis-related proteins were detected by Western blot assay, and apoptosis and reactive oxygen species levels were analyzed by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling. Iron content in myocardial tissue and cells was measured by enzyme-linked immunosorbent assay.

Results: Myocardial I/R increased myocardial infarct size and serum lactate dehydrogenase (LDH) levels compared with the control group, indicating severe myocardial injury. Western blot results showed that MIRI reduced endogenous vaspin and HIF-1α levels and inhibited glutathione peroxidase 4. In vivo and in vitro vaspin overexpression treatment reduced infarct size, decreased LDH levels, inhibited ferroptosis pathway activity, and alleviated oxidative stress levels in myocardial tissues. In the H/R model, vaspin overexpression upregulated HIF-1α, inhibited ferroptosis markers, and reduced apoptosis and iron deposition. However, inhibiting HIF-1α reversed the cardioprotective and anti-ferroptotic effects of vaspin.

Conclusion: Vaspin inhibits ferroptosis and upregulates the HIF-1α signaling pathway to mitigate myocardial I/R injury. The vaspin/HIF-1α pathway could be a potential target for MIRI prevention and treatment and offers fresh perspectives on ischemic heart disease management. Vaspin could be a novel cardioprotective agent that plays a significant role in the prevention and treatment of cardiovascular diseases.