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 firstly found that baicalein attenuated myocardial necrosis in vitro and in vivo, and it significantly suppressed 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 firstly 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 in order to attenuate Cardiomyocyte necrosis.

据报道，心肌细胞坏死是心脏病发病机理的主要组成部分。我们注意到黄ical素是黄cut根中的一种主要成分，通过抑制心肌细胞的氧化应激和凋亡发挥心脏保护作用。但是，很少有人报道黄ical素是否通过抑制坏死发挥心肌保护作用。此外，死亡受体依赖性坏死细胞的死亡是由受体相互作用的丝氨酸/苏氨酸激酶1/3（RIPK1 / RIPK3）介导的。因此，靶向RIPK1 / RIPK3可能代表坏死相关心脏疾病的潜在预防和治疗机会。据报道，Hsc70相互作用蛋白的羧基末端通过其E3泛素连接酶活性在心脏保护中起着重要作用，但是尚不清楚CHIP是否在心肌细胞坏死中调节RIP1K / RIPK3。在我们的研究中，我们首先发现黄ical素可在体内和体外减轻心肌坏死，通过干扰RIPK1 / RIPK3坏死体的形成，明显抑制了氧化应激诱导的心肌坏死。此外，我们验证了CHIP通过泛素化依赖的RIPK3降解抑制了心肌坏死。然后我们首先推测黄ical苷可能促进CHIP的稳定性发挥心脏保护作用，并且我们还发现黄ical苷促进CHIP的E3泛素连接酶活性来负调节RIPK3。两者合计，我们的结果首次揭示了黄ical素在稳定CHIP活性以促进RIPK1 / RIPK3泛素化和降解以减轻心肌细胞坏死中的关键作用。我们验证了CHIP通过泛素化依赖的RIPK3降解抑制了心肌坏死。然后我们首先推测黄ical苷可能促进CHIP的稳定性发挥心脏保护作用，并且我们还发现黄ical苷促进CHIP的E3泛素连接酶活性来负调节RIPK3。两者合计，我们的结果首次揭示了黄ical素在稳定CHIP活性以促进RIPK1 / RIPK3泛素化和降解以减轻心肌细胞坏死中的关键作用。我们验证了CHIP通过泛素化依赖的RIPK3降解抑制了心肌坏死。然后我们首先推测黄ical苷可能促进CHIP的稳定性发挥心脏保护作用，并且我们还发现黄ical苷促进CHIP的E3泛素连接酶活性负调节RIPK3。两者合计，我们的结果首次揭示了黄ical素在稳定CHIP活性以促进RIPK1 / RIPK3泛素化和降解以减轻心肌细胞坏死中的关键作用。