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CXADR-like membrane protein protects against heart injury by preventing excessive pyroptosis after myocardial infarction.

ABSTRACT: Myocardial infarction (MI) results in cardiomyocyte death and ultimately leads to heart failure. Pyroptosis is a type of the inflammatory programmed cell death that has been found in various diseased tissues. However, the role of pyroptosis in MI heart remains unknown. Here, we showed that CXADR-like membrane protein (CLMP) was involved in pyroptosis in the mouse MI heart. Our data showed that CLMP was strongly expressed in fibroblasts of the infarcted mouse hearts. The Clmp^+/- mice showed more serious myocardial fibrosis and ventricular dysfunction post-MI than wild-type (Clmp^+/+ ) mice, indicating a protective effect of the fibroblast-expressed CLMP against MI-induced heart damage. Transcriptome analyses by RNA sequencing indicated that Il-1? mRNA was significantly increased in the MI heart of Clmp^+/- mouse, which indicated a more serious inflammatory response. Meanwhile, cleaved caspase-1 and Gasdermin D were significantly increased in the Clmp^+/- MI heart, which demonstrated enhanced pyroptosis in the Clmp knockdown heart. Further analysis revealed that the pyroptosis mainly occurred in cardiac fibroblasts (CFs). Compared to wild-type fibroblasts, Clmp^+/- CFs showed more serious pyroptosis and inflammatory after LPS plus nigericin treatment. Collectively, our results indicate that CLMP participates in the pyroptotic and inflammatory response of CFs in MI heart. We have provided a novel pyroptotic insight into the ischaemic heart, which might hold substantial potential for the treatment of MI.

SUBMITTER: Han X

PROVIDER: S-EPMC7753842 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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CXADR-like membrane protein protects against heart injury by preventing excessive pyroptosis after myocardial infarction.

Han Xinglong X Zhao Zhen-Ao ZA Yan Shiping S Lei Wei W Wu Hongchun H Lu Xing-Ai XA Chen Yueqiu Y Li Jingjing J Wang Yaning Y Yu Miao M Wang Yongming Y Zheng Yufang Y Wang Hongyan H Shen Zhenya Z Hu Shijun S

Journal of cellular and molecular medicine 20201021 23

Myocardial infarction (MI) results in cardiomyocyte death and ultimately leads to heart failure. Pyroptosis is a type of the inflammatory programmed cell death that has been found in various diseased tissues. However, the role of pyroptosis in MI heart remains unknown. Here, we showed that CXADR-like membrane protein (CLMP) was involved in pyroptosis in the mouse MI heart. Our data showed that CLMP was strongly expressed in fibroblasts of the infarcted mouse hearts. The Clmp<sup>+/-</sup> mice s ...[more]

PMID: 33084169

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Project description:Pyroptosis is a form of inflammatory cell death that could be driven by the nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome activation following myocardial infarction (MI). Emerging evidence suggests the therapeutic potential for ameliorating MI-induced myocardial damages by targeting NLRP3 and pyroptosis. In this study, we investigated the myocardial protection effect of a novel anthraquinone compound (4,5-dihydroxy-7-methyl-9,10-anthraquinone-2-ethyl succinate) named Kanglexin (KLX) in vivo and in vitro. Male C57BL/6 mice were pre-treated either with KLX (20, 40 mg· kg-1per day, intragastric gavage) or vehicle for 7 consecutive days prior to ligation of coronary artery to induce permanent MI. KLX administration dose-dependently reduced myocardial infarct size and lactate dehydrogenase release and improved cardiac function as compared to vehicle-treated mice 24 h after MI. We found that MI triggered NLRP3 inflammasome activation leading to conversion of interleukin-1β (IL-1β) and IL-18 into their active mature forms in the heart, which could expand the infarct size and drive cardiac dysfunction. We also showed that MI induced pyroptosis, as evidenced by increased DNA fragmentation, mitochondrial swelling, and cell membrane rupture, as well as increased levels of pyroptosis-related proteins, including gasdermin D, N-terminal GSDMD, and cleaved caspase-1. All these detrimental alterations were prevented by KLX. In hypoxia- or lipopolysaccharide (LPS)-treated neonatal mouse ventricular cardiomyocytes, we showed that KLX (10 μM) decreased the elevated levels of terminal deoxynucleotidyl transferase dUTP nick end labeling- and propidium iodide-positive cells, and pyroptosis-related proteins. We conclude that KLX prevents MI-induced cardiac damages and cardiac dysfunction at least partly through attenuating NLRP3 and subsequent cardiomyocyte pyroptosis, and it is worthy of more rigorous investigations for its potential for alleviating ischemic heart disease.

Dataset Information

CXADR-like membrane protein protects against heart injury by preventing excessive pyroptosis after myocardial infarction.

Publications

CXADR-like membrane protein protects against heart injury by preventing excessive pyroptosis after myocardial infarction.

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