Department of Physiology, Faculty of Veterinary Science, Chulalongkorn University, Bangkok, Thailand.
Department of Physiology, Faculty of Pharmacy, Mahidol University, Bangkok, Thailand.
Sci Rep. 2023 Jul 16;13(1):11472. doi: 10.1038/s41598-023-38694-6.
Sacubitril/valsartan (SAC/VAL), an angiotensin receptor blocker-neprilysin inhibitor, has been widely used to treat several types of heart failure. Nevertheless, the effects of drugs in mitral regurgitation patients, from the molecular level to therapeutic effects, remain unclear. This study investigates the roles of SAC/VAL on cardiac function, mitochondrial quality, autophagy, mitophagy, and natriuretic peptides in a rat model of chronic mitral regurgitation. Male Sprague-Dawley rats underwent MR induction (n = 16) and sham surgeries (n = 8). Four weeks post-surgery confirmed MR rats were randomly divided into MR (n = 8) and SAC/VAL (n = 8) groups. The SAC/VAL group was administered SAC/VAL, whereas the MR and the sham rats received vehicle via oral gavage daily for 8 weeks. Cardiac geometry, function, and myocardial fibrosis were assessed by echocardiography and histopathology. Spectrophotometry and real-time PCR were performed to assess the pharmacological effects on mitochondrial quality, autophagy, mitophagy, and natriuretic peptides. MR rats demonstrated significant left heart dilation and left ventricular systolic dysfunction compared with the sham group, which could be significantly improved by SAC/VAL. In addition, SAC/VAL significantly reduced myocardial cardiac remodeling and fibrosis in MR rats. SAC/VAL improved the mitochondrial quality by attenuating mitochondrial reactive oxygen species production and mitochondrial depolarization compared with the MR group. Also, the upregulation of autophagy-related, mitophagy-related, and natriuretic peptide system gene expression in MR rats was attenuated by SAC/VAL treatment. In conclusion, this study demonstrated that SAC/VAL treatment could provide numerous beneficial effects in MR conditions, suggesting that this drug may be an effective treatment for MR.
沙库巴曲缬沙坦（SAC/VAL），一种血管紧张素受体阻断剂-脑啡肽酶抑制剂，已被广泛用于治疗多种心力衰竭。然而，药物在二尖瓣反流患者中的作用，从分子水平到治疗效果，仍不清楚。本研究探讨了 SAC/VAL 在慢性二尖瓣反流大鼠模型中心脏功能、线粒体质量、自噬、线粒体自噬和利钠肽的作用。雄性 Sprague-Dawley 大鼠接受 MR 诱导（n=16）和假手术（n=8）。手术后 4 周确认 MR 大鼠随机分为 MR 组（n=8）和 SAC/VAL 组（n=8）。SAC/VAL 组给予 SAC/VAL，MR 和假手术大鼠每日经口灌胃给予载体，持续 8 周。超声心动图和组织病理学评估心脏几何形状、功能和心肌纤维化。分光光度法和实时 PCR 用于评估对线粒体质量、自噬、线粒体自噬和利钠肽的药理学作用。与假手术组相比，MR 大鼠表现出明显的左心扩张和左心室收缩功能障碍，SAC/VAL 可显著改善。此外，SAC/VAL 可显著减轻 MR 大鼠的心肌重塑和纤维化。与 MR 组相比，SAC/VAL 通过减轻线粒体活性氧产生和线粒体去极化来改善线粒体质量。此外，SAC/VAL 治疗还减弱了 MR 大鼠自噬相关、线粒体自噬相关和利钠肽系统基因表达的上调。总之，本研究表明 SAC/VAL 治疗可在 MR 情况下提供多种有益作用，提示该药物可能是治疗 MR 的有效方法。
