Connexin 43(Cx43)is the most important protein in the gap junction channel between cardiomyocytes.Abnormalities of Cx43 change the conduction velocity and direction of cardiomyocytes,leading to reentry and conduction block of the myocardium,thereby causing arrhythmia.It has been shown that IL-1β reduces the expression of Cx43 in astrocytes and cardiomyocytes in vitro.However,whether caspase-1 and IL-1β affect connexin 43 after myocardial infarction(MI)is uncertain.In this study we investigated the effects of VX765,a caspase-1 inhibitor,on the expression of Cx43 and cell-to-cell communication after MI.Rats were treated with VX765(16 mg/kg,i.v.)1 h before the left anterior descending artery(LAD)ligation,and then once daily for 7 days.The ischemic heart was collected for histochemical analysis and Western blot analysis.We showed that VX765 treatment significantly decreased the infarct area,and alleviated cardiac dysfunction and remodeling by suppressing the NLRP3 inflammasome/caspase-1/IL-1βexpression in the heart after Ml.In addition,VX765 treatment markedly raised Cx43 levels in the heart after Ml.In vitro experiments were conducted in rat cardiac myocytes(RCMs)stimulated with the supernatant from LPS/ATP-treated rat cardiac fibroblasts(RCFs).Pretreatment of the RCFs with VX765(25 μM)reversed the downregulation of Cx43 expression in RCMs and significantly improved intercellular communication detected using a scrape-loading/dye transfer assay.We revealed that VX765 suppressed the activation of p38 MAPK signaling in the heart tissue after Ml as well as in RCMs stimulated with the supernatant from LPS/ATP-treated RCFs.Taken together,these data show that the caspase-1 inhibitor VX765 upregulates Cx43 expression and improves cell-to-cell communication in rat heart after Ml via suppressing the IL-1β/p38 MAPK pathway.

Xue-ling Su;Shu-hui Wang;Sumra Komal;Liu-gen Cui;Rui-cong Ni;Li-rong Zhang;Sheng-na Han

Department of Pharmacology,School of Basic Medical Sciences,Zhengzhou University,Zhengzhou 450001,China

中国药理学报（英文版）

[1]Xue-ling Su;Shu-hui Wang;Sumra Komal;Liu-gen Cui;Rui-cong Ni;Li-rong Zhang;Sheng-na Han-.The caspase-1 inhibitor VX765 upregulates connexin 43 expression and improves cell-cell communication after myocardial infarction via suppressing the IL-1β/p38 MAPK pathway)[J].中国药理学报（英文版）,2022(09):2289-2301

VX765,RCMs

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