Department of Cardiology, The First Hospital of China Medical University, Shenyang, 110001 Liaoning, China.
Department of Hepatobiliary Surgery, People's Hospital of China Medical University, Liaoning Provincial People's Hospital, Shenyang, 110016 Liaoning, China.
Oxid Med Cell Longev. 2022 Sep 22;2022:5009289. doi: 10.1155/2022/5009289. eCollection 2022.
Sacubitril valsartan (lcz696) has been demonstrated as a substitute for angiotensin-converting enzyme inhibitors and angiotensin receptor blockers for the treatment of heart failure. This research is aimed at examining the effects of lcz696 and its target molecules on myocardial infarction (MI). A rat model of MI was induced by left anterior descending artery ligation and treated with lcz696. Lcz696 treatment significantly reduced cardiac injury and heart failure, restored the left ventricular fractional shortening and ejection fraction, and reduced oxidative stress and inflammatory responses in rat myocardium. By analyzing the heart failure-related GSE47495 dataset and performing gene ontology (GO) functional enrichment analysis, we obtained histone lysine methyltransferase SUV39H1 and secreted phosphoprotein 1 (SPP1) as two molecules implicated in the oxidative stress and inflammation processes. An elevation of SUV39H1 whereas a decline of SPP1 were detected in cardiac tissues after lcz696 treatment. Enrichments of SUV39H1 and H3K9me3 at the SPP1 promoter were identified by chromatin immunoprecipitation assay. SUV39H1 catalyzed H3K9me3 modification to suppress the expression of SPP1. Preconditioning of SUV39H1 silencing blocked the protective roles of lcz696, but SPP1 silencing alleviated the myocardial injury. In conclusion, this study demonstrates that lcz696 enhances cardiac function and alleviates MI in rats through a SUV39H1/SPP1 axis.
沙库巴曲缬沙坦（LCZ696）已被证明可替代血管紧张素转换酶抑制剂和血管紧张素受体阻滞剂用于心力衰竭的治疗。本研究旨在研究 LCZ696 及其靶分子对心肌梗死（MI）的影响。通过结扎左前降支诱导大鼠 MI 模型，并给予 LCZ696 治疗。LCZ696 治疗显著减轻了心脏损伤和心力衰竭，恢复了左心室缩短分数和射血分数，并减轻了大鼠心肌的氧化应激和炎症反应。通过分析心力衰竭相关的 GSE47495 数据集并进行基因本体（GO）功能富集分析，我们获得了组蛋白赖氨酸甲基转移酶 SUV39H1 和分泌型磷蛋白 1（SPP1）这两个与氧化应激和炎症过程相关的分子。LCZ696 治疗后，心脏组织中 SUV39H1 升高而 SPP1 下降。染色质免疫沉淀检测发现 SUV39H1 和 H3K9me3 在 SPP1 启动子上的富集。SUV39H1 催化 H3K9me3 修饰，抑制 SPP1 的表达。SUV39H1 沉默预处理可阻断 LCZ696 的保护作用，但 SPP1 沉默可减轻心肌损伤。综上所述，本研究表明 LCZ696 通过 SUV39H1/SPP1 轴增强大鼠心功能并减轻 MI。
