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.

冠状动脉微栓塞术 (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以预防 PMI，但其潜在机制尚未确定。在这里，我们检查 NLRP3 炎性体是否有助于 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，患有 CME 的小鼠口服 40 mg/kg/d 瑞舒伐他汀 (RVS) 或腹膜内注射选择性 NLRP3 炎性体抑制剂 MCC950 (20 mg/kg/d)。用 MCC950 和 RVS 治疗的小鼠表现出改善的心脏收缩功能和形态学变化、减少的纤维化和微梗死面积，以及降低的血清乳酸脱氢酶 (LDH) 水平。从机械上讲，RVS 降低了 NLRP3、caspase-1、interleukin-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，在 RVS 处理的小鼠中观察到活性氧 (ROS) 水平降低和线粒体损伤减轻。在体外研究中，RVS 抑制 H9c2 细胞中由肿瘤坏死因子 α 和缺氧诱导的 NLRP3 炎性体的激活。同时，细胞焦亡也被 RVS 抑制，表现为细胞活力增加，H9c2 细胞对 LDH 和碘化丙锭的摄取减少。RVS 还降低了体外线粒体 ROS 生成的水平。我们的研究结果表明，NLRP3 炎症小体依赖性心脏细胞焦亡在 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。我们还揭示了 RVS 在 CME 中的抗细胞焦亡作用，这与调节线粒体 ROS 有关。