Baicalein protects cardiomyocytes from oxidative stress induced programmed necrosis by stabilizing carboxyl terminus of Hsc70-interacting protein

Abstract Cardiomyocyte necrosis has been reported to be a major component in pathogenesis of cardiac diseases. We noticed that baicalein, a kind of principal components in the roots of Scutellaria baicalensis Georgi, exerts cardioprotective effects by inhibiting oxidative stress and apoptosis of Cardiomyocytes. However, it is rarely reported whether baicalein exerts myocardial protection by inhibiting necrosis. In addition, the death receptor-dependent necrotic cell death is mediated by receptor interacting serine/threonine kinase 1/3(RIPK1/RIPK3). Thus, targeting RIPK1/RIPK3 may represent potential preventive and therapeutic opportunities of necrosis-related cardiac diseases. Carboxyl terminus of Hsc70-interacting protein (CHIP) has been reported to play a significant role on cardiac protection through its E3 ubiquitin ligase activity, but it is not clear whether CHIP regulates RIP1K/RIPK3 in cardiomyocytes necrosis. In our study, we first found that baicalein attenuates myocardial necrosis in vitro and vivo, and it significantly suppresses myocardial necrosis induced by oxidative stress through disturbing RIPK1/RIPK3 necrososme formation in vitro. Besides, we verified that CHIP suppressed myocardial necrosis through ubiquitylation-dependent degradation of RIPK3. And then we first speculated that baicalein may promote stability of CHIP to exert cardioprotective effects, and we also found that baicalein promoted the E3 ubiquitin ligase activity of CHIP to negatively regulate RIPK3. Taken together, our results for the first time reveal a pivotal role of baicalein in stabilizing CHIP activity to promote RIPK1/RIPK3 ubiquination and degradation, so that attenuating Cardiomyocyte necrosis.