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

Xue-ling Su1, Shu-hui Wang1, Sumra Komal1, Liu-gen Cui1, Rui-cong Ni1, Li-rong Zhang1, Sheng-na Han1
1 epartment of Pharmacology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China
Correspondence to: Li-rong Zhang:, Sheng-na Han:,
DOI: 10.1038/s41401-021-00845-8
Received: 8 August 2021
Accepted: 15 December 2021
Advance online: 7 February 2022


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-1β expression in the heart after MI. In addition, VX765 treatment markedly raised Cx43 levels in the heart after MI. 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 MI 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 MI via suppressing the IL-1β/p38 MAPK pathway.
Keywords: myocardial infarction; connexin 43; caspase-1; IL-1β; p38 MAPK; VX765; arrhythmia

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