Abstract
Pathological myocardial hypertrophy can induce heart failure with high mortality, it is necessary to explore its pathogenesis. Tripartite motif-containing 26 (TRIM26) belongs to the multidomain E3 ubiquitin ligase family. We observed increased expression of TRIM26 in the myocardium of C57BL/6 mice subjected to transverse aortic constriction (TAC) surgery and neonatal rat cardiomyocytes (NRCMs) treated with phenylephrine (PE). To evaluate the role of TRIM26 in pathological cardiac hypertrophy, we generated Trim26 global knockout mice and Trim26 overexpression adenoviruses. Mice with Trim26 deletion showed alleviated cardiomyocyte enlargement, inflammation, fibrosis, and cardiac dysfunction after TAC surgery. In PE-treated NRCMs, Trim26 overexpression promoted cardiomyocyte enlargement and inflammation, while Trim26 knockdown had the opposite effects. RNA sequencing and molecular biology methodologies were performed to identify targets conducive to TRIM26 function. The results showed that TRIM26 activated the transforming growth factor-beta activated kinase 1 (TAK1)-c-Jun N-terminal kinase/p38 signaling pathway in response to hypertrophic stress. Moreover, inhibition of TAK1 activation can reverse the promotion effect of TRIM26 overexpression on cardiomyocyte hypertrophy induced by PE stimulation in vitro. Our study demonstrated that TRIM26 plays an active role in pathological cardiac hypertrophy, and the TRIM26-TAK1 pathway may represent a therapeutic target for treating pathological cardiac hypertrophy and heart failure.