Jia Tian, Wang Xiaozhi, Tang Yiqun, Yu Wenying, Li Chenhui, Cui Shufang, Zhu Juanjuan, Meng Wei, Wang Chen, Wang Quanyi
State Key Laboratory of Natural Medicines, Department of Life Sciences and Technology, China Pharmaceutical University, Nanjing, China.
Department of Cardiology, The First Affiliated Hospital With Nanjing Medical University, Nanjing, China.
Front Cell Dev Biol. 2021 Oct 29;9:760035. doi: 10.3389/fcell.2021.760035. eCollection 2021.
Heart failure caused by cardiac fibrosis has become a major challenge of public health worldwide. Cardiomyocyte programmed cell death (PCD) and activation of fibroblasts are crucial pathological features, both of which are associated with aberrant Ca influx. Transient receptor potential cation channel subfamily M member 7 (TRPM7), the major Ca permeable channel, plays a regulatory role in cardiac fibrosis. In this study, we sought to explore the mechanistic details for sacubitril, a component of sacubitril/valsartan, in treating cardiac fibrosis. We demonstrated that sacubitril/valsartan could effectively ameliorate cardiac dysfunction and reduce cardiac fibrosis induced by isoprotereno (ISO) . We further investigated the anti-fibrotic effect of sacubitril in fibroblasts. LBQ657, the metabolite of sacubitril, could significantly attenuate transforming growth factor-β 1 (TGF-β1) induced cardiac fibrosis by blocking TRPM7 channel, rather than suppressing its protein expression. In addition, LBQ657 reduced hypoxia-induced cardiomyocyte PCD suppression of Ca influx regulated by TRPM7. These findings suggested that sacubitril ameliorated cardiac fibrosis by acting on both fibroblasts and cardiomyocytes through inhibiting TRPM7 channel.
由心脏纤维化引起的心力衰竭已成为全球公共卫生面临的一项重大挑战。心肌细胞程序性细胞死亡（PCD）和成纤维细胞的激活是关键的病理特征，二者均与异常的钙内流有关。瞬时受体电位阳离子通道M亚家族成员7（TRPM7）作为主要的钙通透通道，在心脏纤维化中发挥调节作用。在本研究中，我们试图探究沙库巴曲缬沙坦的成分之一沙库巴曲治疗心脏纤维化的具体机制。我们证明，沙库巴曲缬沙坦可有效改善心脏功能障碍，并减轻异丙肾上腺素（ISO）诱导的心脏纤维化。我们进一步研究了沙库巴曲对成纤维细胞的抗纤维化作用。沙库巴曲的代谢产物LBQ657可通过阻断TRPM7通道，而非抑制其蛋白表达，显著减轻转化生长因子-β1（TGF-β1）诱导的心脏纤维化。此外，LBQ657可减少缺氧诱导的心肌细胞PCD，抑制由TRPM7调节的钙内流。这些发现表明，沙库巴曲通过抑制TRPM7通道作用于成纤维细胞和心肌细胞，从而改善心脏纤维化。
