Iguratimod Alleviates Myocardial Ischemia/Reperfusion Injury Through Inhibiting Inflammatory Response Induced by Cardiac Fibroblast Pyroptosis via COX2/NLRP3 Signaling Pathway.
Iguratimod Alleviates Myocardial Ischemia/Reperfusion Injury Through Inhibiting Inflammatory Response Induced by Cardiac Fibroblast Pyroptosis via COX2/NLRP3 Signaling Pathway.
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艾拉莫德通过 COX2/NLRP3 信号通路抑制心脏成纤维细胞焦亡诱导的炎症反应，减轻心肌缺血/再灌注损伤
DOI：
10.3389/fcell.2021.746317
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发表时间：
2021
影响因子：
5.5
通讯作者：
Ji FH
中科院分区：
文献类型：
--
作者：
Zhang M;Lei YS;Meng XW;Liu HY;Li LG;Zhang J;Zhang JX;Tao WH;Peng K;Lin J;Ji FH
背景：NLRP 3炎性小体在缺血再灌注损伤中参与了无菌性炎症反应和细胞凋亡。心脏成纤维细胞（cardiac fibroblast，CFs）被认为是半专职性炎症细胞，在心脏中发挥免疫调节作用。艾拉莫德通过发挥强大的抗炎作用在几种人类疾病中提供保护作用。然而，目前尚不清楚iguratimod是否可以减轻心肌I/R损伤，以及NLRP 3相关的CFs焦亡是否参与了这一过程。研究方法：对GSE 160516数据集进行转录组学分析，探讨心肌I/R过程中差异表达基因的生物学功能。在体内，结扎小鼠冠状动脉左前降支30 min，再灌注24 h。在体外，原代CFs进行缺氧1小时，然后复氧3小时（H/R）。在I/R或H/R之前使用艾拉莫德。检测心肌梗死面积、血清肌钙蛋白I（cTnI）水平、心肌组织病理学、细胞活力、乳酸脱氢酶（LDH）释放、心肌细胞凋亡相关分子mRNA和蛋白表达水平。免疫荧光法检测NLRP 3蛋白在心肌组织中的细胞定位。结果如下：在心肌I/R过程中，炎症反应被认为是最重要的生物学过程，而核苷酸结合寡聚化结构域（NOD）样受体信号通路是介导心肌炎症反应的重要途径。在我们的实验中，iguratimod预处理显著改善I/R诱导的心肌损伤和H/R诱导的CFs焦亡，如心肌梗死面积减少，血清cTnI水平降低，上清液中LDH释放，以及改善心脏组织病理学和细胞活力。免疫荧光分析显示NLRP 3主要定位于CFs。此外，iguratimod抑制促炎性细胞因子和热解相关分子的表达，包括NLRP 3、裂解的半胱天冬酶-1和GSDMD-N。结论：NOD样受体介导的炎症反应在心肌I/R损伤中起重要作用。艾拉莫德通过COX2/NLRP3信号通路抑制心脏成纤维细胞焦亡，从而减少心脏炎症级联反应，从而保护心肌细胞。
Background: NLRP3 inflammasome contributes a lot to sterile inflammatory response and pyroptosis in ischemia/reperfusion (I/R) injury. Cardiac fibroblasts (CFs) are regarded as semi-professional inflammatory cells and they exert an immunomodulatory role in heart. Iguratimod provides a protective role in several human diseases through exerting a powerful anti-inflammatory effect. However, it is still unclear whether iguratimod could alleviate myocardial I/R injury and whether inflammation triggered by NLRP3-related pyroptosis of CFs is involved in this process. Methods: Transcriptomics analysis for GSE160516 dataset was conducted to explore the biological function of differentially expressed genes during myocardial I/R. In vivo, mice underwent ligation of left anterior descending coronary artery for 30 min followed by 24 h reperfusion. In vitro, primary CFs were subjected to hypoxia for 1 h followed by reoxygenation for 3 h (H/R). Iguratimod was used prior to I/R or H/R. Myocardial infarct area, serum level of cardiac troponin I (cTnI), pathology of myocardial tissue, cell viability, lactate dehydrogenase (LDH) release, and the expression levels of mRNA and protein for pyroptosis-related molecules were measured. Immunofluorescence was applied to determine the cellular localization of NLRP3 protein in cardiac tissue. Results: During myocardial I/R, inflammatory response was found to be the most significantly enriched biological process, and nucleotide-binding oligomerization domain (NOD)-like receptor signaling was a crucial pathway in mediating cardiac inflammation. In our experiments, pretreatment with iguratimod significantly ameliorated I/R-induced myocardial injury and H/R-induced pyroptosis of CFs, as evidenced by reduced myocardial infarct area, serum cTnI level, and LDH release in supernatants, as well as improved pathology of cardiac tissue and cell viability. Immunofluorescence analysis showed that NLRP3 was mainly localized in CFs. Moreover, iguratimod inhibited the expression of pro-inflammatory cytokines and pyroptosis-related molecules, including NLRP3, cleaved caspase-1, and GSDMD-N. Conclusion: Our results suggested that inflammatory response mediated by NOD-like receptor signaling is of vital importance in myocardial I/R injury. Iguratimod protected cardiomyocytes through reducing the cascade of inflammation in heart by inhibiting cardiac fibroblast pyroptosis via the COX2/NLRP3 signaling pathway.
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DOI：
10.1016/j.bbrc.2017.08.060
发表时间：
2017-11-04
影响因子：
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影响因子：
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