基于瘦素介导PI3K/Akt信号通路研究6-姜酚治疗心肌缺血/再灌注损伤的机制

Our previous studies showed that leptin overexpression is closely related to MIRI, leptin pretreatment may be through the PI3K/Akt signaling pathway inhibition of cardiomyocyte apoptosis attenuate MIRI. The experience in the famous doctors Sini Decoction ginger extract 6-Gingerol can reduced leptin overexpression and MIRI, but the mechanism is not clear. Based on this hypothesis, 6-Gingerol attenuates cardiomyocyte apoptosis by down-regulating leptin expression, up-regulating leptin-mediated PI3K/Akt signaling pathway, and inhibiting cardiomyocyte apoptosis. In order to testify this hypothesis, firstly, the mouse MIRI model and HCM model will be established, and studying the relationship between 6-Gingerol attenuates MIRI and cardiomyocyte apoptosis. Secondly, the molecular mechanism of 6-Gingerol mitigating cardiomyocyte apoptosis will be explored in vivo and in vitro by using PI3K gene knockout mouse MIRI model and HCM model . Finally, to elucidate the molecular mechanism of 6-Gingerol targeting leptin on PI3K/Akt signaling pathway in cardiomyocyte apoptosis in vivo and in vitro by using leptin overexpression and knockout mouse MIRI model and HCM model. This study will explore the mechanism of 6-Gingerol in the treatment of MIRI by leptin-mediated PI3K/Akt signaling pathway, and provide experimental evidences for the development of 6-Gingerol as a drug and its clinical application.

我们前期工作提示瘦素过表达参与MIRI，瘦素预处理可能通过PI3K/Akt信号通路抑制心肌细胞凋亡减轻MIRI；名医经验方四逆汤中干姜提取物6-姜酚能抑制瘦素过表达、减轻MIRI，但机制尚不明确。据此假说：6-姜酚通过抑制瘦素过表达，上调瘦素介导的PI3K/Akt信号通路表达，抑制心肌细胞凋亡，减轻MIRI。为验证假说，首先，利用小鼠MIRI模型和HCM模型，明确6-姜酚减轻MIRI的作用与抑制心肌细胞凋亡之间的关系。其次，利用PI3K基因敲除的小鼠MIRI模型和HCM模型，体内外探讨6-姜酚抑制心肌细胞凋亡的分子机制。最后，利用瘦素基因过表达和敲除的小鼠MIRI模型和HCM模型，体内外阐明6-姜酚靶向瘦素调控PI3K/Akt信号通路表达影响心肌细胞凋亡的分子机制。本项目以瘦素介导的PI3K/Akt信号通路为切入点，探讨6-姜酚治疗MIRI的机制，为6-姜酚开发成药和临床应用提供实验依据。

急性心肌梗死（AMI）后经皮冠状动脉介入术（PCI） 、溶栓疗法等及时恢复心肌血液供应对于减轻梗死后心肌重塑依然是最有效的治疗方法。然而，缺血的心肌在开放循环后可出现心脏功能、代谢及结构上的损伤，即心肌缺血/再灌注损伤（MIRI），严重时可导致严重心律失常、心力衰竭甚至心脏性猝死 。再灌注引起心肌细胞死亡方式包括坏死、凋亡、胀亡，而凋亡是心肌细胞死亡的重要方式，如能抑制凋亡即能减轻MIRI。因此，有效抑制心肌细胞凋亡对治疗MIRI具有重要意义。我们前期研究发现，6-姜酚（6-Gingerol）和瘦素（Leptin）能够减轻MIRI，但具体机制不详。因此我们深入探索6-姜酚是否通过影响瘦素表达调控PI3K/Akt信号通路参与MIRI。研究结果发现：1、6-姜酚通过调控PI3K/Akt信号通路抑制心肌细胞凋亡减轻MIRI。2、瘦素通过调控PI3K/Akt信号通路抑制心肌细胞凋亡减轻MIRI。3、瘦素通过诱导心肌自噬减轻MIRI。此研究成果为揭示MIRI这一重要临床病理过程的发病及防治提供重要的理论依据。未来通过本研究的推广应用，能有效改善MIRI性疾病治疗的疗效，在临床MIRI性疾病的预防及治疗上具有很大的实用价值和广泛的发展前景，并产生相应的社会效益和经济效益，同时也有利于心血管学科建设。