Capn4 aggravates angiotensin II-induced cardiac hypertrophy by activating the IGF-AKT signalling pathway.

Yuanping Cao, Qun Wang, Caiyun Liu, Wenjun Wang, Songqing Lai, Huaxi Zou, Ende Tao, Fudong Wang, Li Wan

Journal of biochemistry 2022 Jan 07

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Capn4 belongs to a family of calpains that participate in a wide variety of biological functions, but little is known about the role of Capn4 in cardiac disease. Here, we show that the expression of Capn4 was significantly increased in Angiotensin II (Ang II)-treated cardiomyocytes and Ang II-induced cardiac hypertrophic mouse hearts. Importantly, in agreement with the Capn4 expression patterns, the maximal calpain activity measured in heart homogenates was elevated in Ang II-treated mice and oral coadministration of SNJ-1945 (calpain inhibitor) attenuated the total calpain activity measured in vitro. Functional assays indicated that overexpression of Capn4 obviously aggravated Ang II-induced cardiac hypertrophy, whereas Capn4 knockdown resulted in the opposite phenotypes. Further investigation demonstrated that Capn4 maintained the activation of the insulin-like growth factor (IGF)-AKT signalling pathway in cardiomyocytes by increasing c-Jun expression. Mechanistic investigations revealed that Capn4 directly bound and stabilized c-Jun and knockdown of Capn4 increased the ubiquitination level of c-Jun in cardiomyocytes. Additionally, our results demonstrated that the antihypertrophic effect of Capn4 silencing was partially dependent on the inhibition of c-Jun. Overall, these data suggested that Capn4 contributes to cardiac hypertrophy by enhancing the c-Jun-mediated IGF-AKT signalling pathway and could be a potential therapeutic target for hypertrophic cardiomyopathy. © The Author(s) 2021. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved.

Citation

Yuanping Cao, Qun Wang, Caiyun Liu, Wenjun Wang, Songqing Lai, Huaxi Zou, Ende Tao, Fudong Wang, Li Wan. Capn4 aggravates angiotensin II-induced cardiac hypertrophy by activating the IGF-AKT signalling pathway. Journal of biochemistry. 2022 Jan 07;171(1):53-61