Targeting interleukin-21 inhibits stress overload-induced cardiac remodelling via the TIMP4/MMP9 signalling pathway.

Yun Xing, Saiyang Xie, Wenke Shi, Xiaofeng Zeng, Wei Deng, Qizhu Tang

European journal of pharmacology 2023 Feb 05

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Increased inflammatory mediators produced by inflamed cells are often connected with pressure-induced cardiac remodelling and heart failure. Interleukin-21 (IL-21) serves as an immunomodulator involved in multiple pathological processes, while the role of IL-21 in pressure-induced cardiac remodelling remains unclear. Cardiac function, CD4+T-cell infiltration, and IL-21 and IL-21 receptor expression levels were investigated in a pressure overload mouse model induced by aortic banding (AB) surgery. Western blotting and qPCR were used to detect the effects of IL-21 on inflammation, apoptosis, and fibrosis in the myocardium after AB surgery. In addition, the signal transduction mechanisms underlying these effects were investigated in vivo and in vitro by qPCR and western blotting. IL-21 levels in mice rapidly increased in the acute phase after AB surgery. Compared with those in the control group, the transverse aortas of mice in the AB surgery group contracted. However, it must be noted that neutralizing IL-21 could reduce myocardial injury and remodelling, while the administration of exogenous IL-21 recombinant protein had the opposite effect. Mechanistically, we learned that IL-21 is effective in inducing the activation of tissue inhibitor of metalloproteinase 4 (TIMP4) and matrix metalloproteinase 9 (MMP-9) signalling in vitro and in vivo. We believe that increased activation and secretion of IL-21 and CD4+ T cells may contribute to stress overload-induced cardiac remodelling. These findings reveal a novel mechanism by which IL-21 stimulates myocardial inflammation, apoptosis, and fibrosis to induce stress-overload-induced myocardial remodelling by activating the TIMP4/MMP9 signalling pathway. Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.

Citation

Yun Xing, Saiyang Xie, Wenke Shi, Xiaofeng Zeng, Wei Deng, Qizhu Tang. Targeting interleukin-21 inhibits stress overload-induced cardiac remodelling via the TIMP4/MMP9 signalling pathway. European journal of pharmacology. 2023 Feb 05;940:175482