Sestrin2 Regulates Mitochondrial Function and Autophagy via Nrf2/SIRT3 Signaling to Ameliorate Hypoxia/Reoxygenation-Induced Rat's Cardiomyocyte Injury

Mitigating myocardial ischemia-reperfusion (I/R) injury poses a significant challenge, necessitating the exploration of novel therapeutic targets. Sestrin2 (Sesn2), a stress-induced protein, has emerged as a potential candidate for attenuating I/R injury, yet its precise mechanisms remain elusive. The role of Sesn2 was investigated using an in vitro model of H9C2 cardiomyocytes subjected to hypoxia-reoxygenation (H/R). Sesn2 expression was modulated through overexpression techniques, and cellular responses, including cell viability, inflammatory factor production, mitochondrial function, oxidative stress, Autophagy, and Apoptosis, were assessed. Furthermore, the role of the Nrf2/SIRT3 signaling pathway in the mechanism was explored via treating cells with Nrf2 inhibitor ML385. Sesn2 overexpression significantly improved cell viability, attenuated inflammatory factor production, preserved mitochondrial function, and mitigated oxidative stress in H/R-exposed cardiomyocytes. Additionally, Sesn2 enhanced Autophagy and modulated the Nrf2/SIRT3 signaling pathway. Moreover, Sesn2-mediated protection was reversed upon inhibition of Nrf2 signaling, underscoring the importance of this pathway in Sesn2-induced protection. Our findings may elucidate the mechanism of Sesn2-mediated protection and highlight its potential as a therapeutic target to ameliorate H/R-induced cardiomyocyte injury.

I/R injury; Nrf2/SIRT3; Sestrin2; autophagy; mitochondrial function.