Nuanxinkang prevents the development of myocardial infarction-induced chronic heart failure by promoting PINK1/Parkin-mediated mitophagy
Nuanxinkang prevents the development of myocardial infarction-induced chronic heart failure by promoting PINK1/Parkin-mediated mitophagy
复制标题
暖心康通过促进PINK 1/Parkin介导的线粒体自噬预防心肌梗死后慢性心力衰竭的发生
DOI：
10.1016/j.phymed.2022.154494
复制
发表时间：
2022-10-21
期刊：
影响因子：
7.9
通讯作者：
Chen, Zixin
中科院分区：
文献类型：
--
作者：
Guan, Zhuoji;Chen, Jie;Chen, Zixin
背景：线粒体功能障碍是慢性心力衰竭（CHF）的重要病理特征。调节线粒体自噬可以有效维持线粒体稳态和能量代谢，从而抑制CHF的发生。暖心康（NXK）是一种中药复方制剂，对CHF具有显着的心脏保护作用；然而，其线粒体自噬的潜在机制尚未完全阐明。本研究旨在探讨NXK治疗心肌梗死（MI）诱发CHF的机制。方法：采用左冠状动脉前降支（LAD）结扎手术建立雄性C57BL/6小鼠心肌梗死（MI）诱发CHF模型。术后第1天起，小鼠灌胃NXK（0.41、0.82或1.65 g/kg/d）、培哚普利（PDPL，0.607 mg/kg/d）或等量无菌水，连续28天。然后检查小鼠的心功能、心肌纤维化、心肌细胞凋亡、心肌细胞线粒体结构和线粒体自噬水平等。此外，利用野生型（WT）小鼠的HL-1心肌细胞建立缺氧损伤模型。使用或不使用含 NXK 的血清预处理 HL-1 细胞。检查 HL-1 细胞中的线粒体功能和线粒体自噬水平。结果：在 MI 诱导的 CHF 小鼠中，观察到心功能障碍、严重心脏重塑、氧化应激水平升高、ATP 水平降低以及 PINK1/Parkin 介导的线粒体自噬抑制。大剂量NXK治疗（1.65 g/kg/d）显着改善MI小鼠心肌能量代谢，抑制心脏重塑，改善心功能，并在一定程度上恢复心脏PINK1/Parkin介导的线粒体自噬水平。在体外，在缺氧的 HL-1 细胞中观察到线粒体活性氧 (ROS) 水平升高且线粒体膜电位 (AIPm) 受损。而 NXK 治疗显着保护心肌细胞免受缺氧引起的线粒体功能障碍，这与体内结果一致。进一步的研究表明，NXK可以增加心肌细胞中PINK1/Parkin介导的线粒体自噬水平，而线粒体自噬抑制剂Mdivi-1可以阻断这一水平。结论：综上所述，NXK可以通过促进Pink1/Parkin介导的线粒体自噬来预防心肌线粒体功能障碍，改善心功能，从而对抗心肌梗死引起的CHF，这代表了一种非常有前景的治疗CHF的策略。
Background: Mitochondrial dysfunction is an important pathological feature of chronic heart failure (CHF). Regulation of mitophagy can effectively maintain mitochondrial homeostasis and energy metabolism, thereby inhibiting the development of CHF. Nuanxinkang (NXK), a Chinese herbal compound preparation, has significant cardioprotective effects on CHF; however, its underlying mechanism on mitophagy has not been completely clarified. This research intended to investigate the mechanism of NXK in treating myocardial infarction (MI)-induced CHF.Methods: The left anterior descending coronary artery (LAD) ligation surgery was performed to establish an MI-induced CHF model in male C57BL/6 mice. From 1 day after surgery, mice were given NXK (0.41, 0.82 or 1.65 g/ kg/d), Perindopril (PDPL, 0.607 mg/kg/d), or an equivalent amount of sterile water by gavage for 28 continuous days. Then, mice were examined for cardiac function, myocardial fibrosis, cardiomyocyte apoptosis, mitochondrial structure and mitophagy levels of cardiomyocytes, etc. In addition, a hypoxic injury model was created using HL-1 cardiomyocytes from wild-type (WT) mice. HL-1 cells were pretreated with or without NXK-containing serum. Mitochondrial function and mitophagy levels were examined in HL-1 cells.Results: In MI-induced CHF mice, cardiac dysfunction, severe cardiac remodeling, elevated levels of oxidative stress, reduced ATP levels, and inhibition of PINK1/Parkin-mediated mitophagy were observed. High-dose NXK treatment (1.65 g/kg/d) significantly improved myocardial energy metabolism, inhibited cardiac remodeling, improved cardiac function, and restored cardiac PINK1/Parkin-mediated mitophagy levels to some extent in MI mice. In vitro, elevated levels of mitochondrial reactive oxygen species (ROS) with impaired mitochondrial membrane potential (AIPm) were observed in hypoxic HL-1 cells. While NXK treatment significantly protected cardiomyocytes from hypoxia-induced mitochondrial dysfunction, which is consistent with the in vivo results. Further studies showed that NXK could increase PINK1/Parkin-mediated mitophagy levels in cardiomyocytes, which could be blocked by the mitophagy inhibitor Mdivi-1.Conclusion: In conclusion, NXK could prevent cardiac mitochondrial dysfunction and improve cardiac function against MI-induced CHF by promoting Pink1/Parkin-mediated mitophagy, which represents a very prospective strategy for the treatment of CHF.