Inhibition of cathepsin S attenuates myocardial ischemia/reperfusion injury by suppressing inflammation and apoptosis
Inhibition of cathepsin S attenuates myocardial ischemia/reperfusion injury by suppressing inflammation and apoptosis
复制标题
抑制组织蛋白酶 S 通过抑制炎症和细胞凋亡来减轻心肌缺血/再灌注损伤
DOI：
10.1002/jcp.29938
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发表时间：
2021-02-01
影响因子：
5.6
通讯作者：
Xia, Zhengyuan
中科院分区：
文献类型：
--
作者：
Peng, Ke;Liu, Hong;Xia, Zhengyuan
心肌缺血/再灌注（I/R）损伤导致高死亡率和发病率，这是由于对潜在机制的不完全理解以及随之而来的缺乏有效治疗。本研究揭示并验证了与心肌I/R损伤相关的炎症和细胞凋亡途径相关的关键候选基因。基于蛋白质-蛋白质相互作用分析，组织蛋白酶S被鉴定为顶部枢纽蛋白，因此，其在心肌I/R损伤中的作用被进一步研究。小鼠心肌I/R导致心肌损伤生物标志物（心肌肌钙蛋白I、乳酸脱氢酶和肌酐激酶-MB）和炎性细胞因子（白细胞介素-1 β [IL-1β]、IL-6和肿瘤坏死因子-α）水平显著升高，细胞凋亡率升高，裂解型半胱天冬酶-8、裂解型半胱天冬酶-3和裂解型聚ADP-核糖聚合酶的蛋白表达上调。上述变化被两种不同的选择性组织蛋白酶S抑制剂LY 3000328或MIV-247阻断。此外，Kaplan-Meier生存曲线显示，组织蛋白酶S抑制剂可改善心肌I/R损伤后的21天生存率。该研究表明，抑制组织蛋白酶S通过抑制炎症和凋亡减轻心肌I/R诱导的损伤，这可能用于心脏保护的临床应用。
Myocardial ischemia/reperfusion (I/R) injury leads to high mortality and morbidity due to the incomplete understanding of the underlying mechanism and the consequent lack of effective therapy. The present study revealed and validated key candidate genes in relation to inflammation and apoptosis pathways underlying myocardial I/R injury. Cathepsin S was identified as the top hub protein based on the protein–protein interaction analysis, and, thus, its role during myocardial I/R injury was further investigated. Myocardial I/R in mice resulted in significantly increased levels of myocardial injury biomarkers (cardiac troponin I, lactic dehydrogenase, and creatinine kinase‐MB) and inflammatory cytokines (interleukin‐1β [IL‐1β], IL‐6, and tumor necrosis factor‐α), elevated apoptosis rate, and upregulated protein expression of cleaved caspase‐8, cleaved caspase‐3, and cleaved poly ADP‐ribose polymerase. These abovementioned changes were blocked by two different selective cathepsin S inhibitors, LY3000328 or MIV‐247. Moreover, Kaplan–Meier survival plot showed that cathepsin S inhibition improved 21‐day survival rate following myocardial I/R injury. This study demonstrated that the inhibition of cathepsin S alleviated myocardial I/R‐induced injury by suppressing inflammation and apoptosis, which may be used in clinical applications of cardioprotection.