Rosuvastatin protects against coronary microembolization-induced cardiac injury via inhibiting NLRP3 inflammasome activation.
Rosuvastatin protects against coronary microembolization-induced cardiac injury via inhibiting NLRP3 inflammasome activation.
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瑞舒伐他汀通过抑制 NLRP3 炎性体激活来预防冠状动脉微栓塞引起的心脏损伤
DOI：
10.1038/s41419-021-03389-1
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发表时间：
2021-01-12
影响因子：
9
通讯作者：
Ge J
中科院分区：
文献类型：
--
作者：
Chen A;Chen Z;Zhou Y;Wu Y;Xia Y;Lu D;Fan M;Li S;Chen J;Sun A;Zou Y;Qian J;Ge J
冠状动脉微栓塞（CME）是围手术期心肌梗死（PMI）的常见原因，具有非常重要的预后意义。然而，与CME相关的分子机制在很大程度上仍然难以捉摸。他汀类药物已被证明可预防PMI，但其潜在机制尚未确定。在这里，我们研究NLRP3炎症小体是否参与CME诱导的心脏损伤，并研究他汀类药物治疗对CME的影响。在体内研究中，CME小鼠口服40 mg/kg/d瑞舒伐他汀（RVS）或选择性NLRP3炎性体抑制剂MCC950 （20 mg/kg/d）。MCC950和RVS均能改善小鼠心肌收缩功能和形态学改变，减少纤维化和微梗死面积，降低血清乳酸脱氢酶（LDH）水平。机制上，RVS降低NLRP3、caspase-1、白介素-1β和Gasdermin D n末端结构域的表达。蛋白质组学分析显示，RVS恢复了CME的能量代谢和氧化磷酸化。此外，rvs处理小鼠的活性氧（ROS）水平降低，线粒体损伤减轻。体外实验表明，RVS可抑制肿瘤坏死因子α +缺氧诱导的H9c2细胞NLRP3炎性体的活化。同时，RVS对H9c2细胞的焦亡也有抑制作用，表现为提高细胞活力，降低LDH和碘化丙啶的摄取。RVS还降低了线粒体ROS的体外生成水平。结果表明NLRP3炎症小体依赖性心脏焦亡在CME诱导的心脏损伤中起重要作用，其抑制剂在CME后发挥心脏保护作用。我们还发现RVS在CME中的抗焦亡作用，这与调节线粒体ROS有关。
Coronary microembolization (CME), a common reason for periprocedural myocardial infarction (PMI), bears very important prognostic implications. However, the molecular mechanisms related to CME remain largely elusive. Statins have been shown to prevent PMI, but the underlying mechanism has not been identified. Here, we examine whether the NLRP3 inflammasome contributes to CME-induced cardiac injury and investigate the effects of statin therapy on CME. In vivo study, mice with CME were treated with 40 mg/kg/d rosuvastatin (RVS) orally or a selective NLRP3 inflammasome inhibitor MCC950 intraperitoneally (20 mg/kg/d). Mice treated with MCC950 and RVS showed improved cardiac contractile function and morphological changes, diminished fibrosis and microinfarct size, and reduced serum lactate dehydrogenase (LDH) level. Mechanistically, RVS decreased the expression of NLRP3, caspase-1, interleukin-1β, and Gasdermin D N-terminal domains. Proteomics analysis revealed that RVS restored the energy metabolism and oxidative phosphorylation in CME. Furthermore, reduced reactive oxygen species (ROS) level and alleviated mitochondrial damage were observed in RVS-treated mice. In vitro study, RVS inhibited the activation of NLRP3 inflammasome induced by tumor necrosis factor α plus hypoxia in H9c2 cells. Meanwhile, the pyroptosis was also suppressed by RVS, indicated by the increased cell viability, decreased LDH and propidium iodide uptake in H9c2 cells. RVS also reduced the level of mitochondrial ROS generation in vitro. Our results indicate the NLRP3 inflammasome-dependent cardiac pyroptosis plays an important role in CME-induced cardiac injury and its inhibitor exerts cardioprotective effect following CME. We also uncover the anti-pyroptosis role of RVS in CME, which is associated with regulating mitochondrial ROS.
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影响因子：
14
作者：
Marinescu, Mark A.;Loffler, Adrian I.;Ouellette, Michelle;Smith, Lavone;Kramer, Christopher M.;Bourque, Jamieson M.
通讯作者：
Bourque, Jamieson M.
内皮细胞焦亡通过 HMGB1/RAGE/cathespin B 信号通路和 NLRP3 炎症小体激活在川崎病中发挥重要作用
影响因子：
9
作者：
Jia, Chang;Zhang, Jian;Chu, Maoping
通讯作者：
Chu, Maoping
影响因子：
39.3
作者：
Fokkema, Marieke L.;Vlaar, Pieter J.;Zijlstra, Felix
通讯作者：
Zijlstra, Felix
影响因子：
4.8
作者：
Limbruno, U;De Carlo, M;De Caterina, R
通讯作者：
De Caterina, R
影响因子：
39.3
作者：
Canton, M;Skyschally, A;Heusch, G
通讯作者：
Heusch, G