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Inhibition of calpain alleviates coxsackievirus B3-induced myocarditis through suppressing the canonical NLRP3 inflammasome/caspase-1-mediated and noncanonical caspase-11-mediated pyroptosis pathways.

Abstract：

:This study aimed to verify the effects of calpain on coxsackievirus B3 (CVB3)-induced myocarditis and to further explore the underlying mechanisms. Transgenic mice overexpressing calpastatin, the endogenous calpain inhibitor, were introduced in the present study. The murine model of viral myocarditis (VMC) was established by intraperitoneal injection of CVB3 into transgenic and wild-type mice. Myocardial injury was measured by H&E staining and ELISA for cTnI. CVB3 replication was assessed via capsid protein VP1 detection and virus titration. The fibrotic factors collagen and TGF-β1 were evaluated by Masson staining and real-time PCR analysis, respectively. Moreover, the levels of NLRP3, AIM2, ASC, cleaved caspase-1, cleaved caspase-11 and the pyroptosis indicators GSDMD p30, IL-1β and HMGB1 were determined by real-time PCR, western blot or immunohistochemical analysis. In addition, peripheral IL-1β and HMGB1 were evaluated by ELISA. We observed that CVB3-infected transgenic mice had lower pathological scores, peripheral cTnI levels, viral loads and expression levels of collagen and TGF-β1 in the heart than CVB3-infected wild-type mice. Furthermore, we found decreased levels of NLRP3, ASC, cleaved caspase-1 and cleaved caspase-11 in the hearts of CVB3-infected transgenic mice. However, after CVB3 infection, the levels of AIM2 in transgenic mice and wild-type mice did not differ significantly. Additionally, calpastatin overexpression significantly reduced the levels of GSDMD p30, IL-1β and HMGB1 in the myocardium as well as peripheral IL-1β and HMGB1. Taken together, these findings indicate that calpain inhibition attenuates CVB3-induced myocarditis by suppressing the canonical NLRP3 inflammasome/caspase-1-mediated and noncanonical caspase-11-mediated pyroptosis pathways.

journal_name

Am J Transl Res

journal_title

American journal of translational research

authors

Yu Y,Shi H,Yu Y,Liu M,Li M,Liu X,Wang Y,Chen R

subject

Has Abstract

pub_date

2020-05-15 00:00:00

pages

1954-1964

issue

issn

1943-8141

journal_volume

pub_type

杂志文章

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Inhibition of calpain alleviates coxsackievirus B3-induced myocarditis through suppressing the canonical NLRP3 inflammasome/caspase-1-mediated and noncanonical caspase-11-mediated pyroptosis pathways.