SESN2-mediated AKT/GSK-3β/NRF2 Activation to Ameliorate Adriamycin Cardiotoxicity in High Fat Diet-induced Obese Mice.

AIMS: Obese patients are highly sensitive to adriamycin (ADR)-induced cardiotoxicity. However, the potential mechanism of superimposed toxicity remains to be elucidated. Sestrin 2 (SESN2), a potential antioxidant, could attenuate stress-induced cardiomyopathy; therefore, this study aims to explore whether SESN2 enhances cardiac resistance to ADR-induced oxidative damage in high fat diet (HFD)-induced obese mice.

RESULTS: The results revealed that obesity decreased SESN2 expression in ADR-exposed heart. And, HFD mice may predispose to ADR-induced cardiotoxicity which probably associated with inhibiting AKT, GSK-3β phosphorylation and subsequently blocking nuclear localization of NRF2, ultimately resulting in cardiac oxidative damage. However, these destructive cascades and cardiac damaged effects induced by HFD/sodium palmitate combined with ADR were blocked by overexpression of SESN2. Moreover, the antioxidant effect of SESN2 could be largely abolished by sh-Nrf2 or wortmannin, respectively. And sulforaphane (SFN), an NRF2 agonist, could remarkably reverse cardiac pathological and functional abnormalities caused by ADR in obese mice.

INNOVATION AND CONCLUSION: The present study demonstrated that SESN2 might be a promising therapeutic target for improving anthracycline-related cardiotoxicity in obesity by up-regulating activity of NRF2 via AKT/GSK-3β/FYN signaling pathway.