Tripartite motif 38 attenuates cardiac fibrosis after myocardial infarction by suppressing TAK1 activation via TAB2/3 degradation

Zhengri Lu; Chunshu Hao; Hao Qian; Yuanyuan Zhao; Xiangwei Bo; Yuyu Yao; Genshan Ma; Lijuan Chen

doi:10.1016/j.isci.2022.104780

Tripartite motif 38 attenuates cardiac fibrosis after myocardial infarction by suppressing TAK1 activation via TAB2/3 degradation

iScience. 2022 Jul 19;25(8):104780. doi: 10.1016/j.isci.2022.104780. eCollection 2022 Aug 19.

Authors

Zhengri Lu¹, Chunshu Hao¹, Hao Qian¹, Yuanyuan Zhao¹, Xiangwei Bo¹, Yuyu Yao¹, Genshan Ma¹, Lijuan Chen^{1

2}

Affiliations

¹ Department of Cardiology, Zhongda Hospital, Southeast University, Nanjing, China.
² Department of Cardiology, Zhongda Hospital Lishui Branch, Southeast University, Nanjing, China.

Abstract

The role of tripartite motif (TRIM) 38, a ubiquitin E3 ligase regulating various pathophysiological processes, in cardiac fibrosis remains unclear. Here, a model of angiotensin II and myocardial infarction (MI)-induced fibrosis was established to explore its role in cardiac fibrosis and its underlying mechanisms. Cardiac fibrosis in the mouse MI model was mitigated by TRIM38 overexpression, but aggravated by its depletion. Consistently, in vitro overexpression or knockdown of TRIM38 ameliorated or aggravated the proliferation and secretion of cardiac fibroblasts (CFs) exposed to fibrotic stimulation, respectively. Mechanistically, TRIM38 suppressed cardiac fibrosis progression by attenuating TAK1/MAPK signaling. Inhibiting TAK1/MAPK signaling with a pharmacological inhibitor greatly reversed the effects of TRIM38 knockdown on CF secretion. Specifically, TRIM38 interacted with and "targeted" TAB2 and TAB3 for degradation, subsequently inhibiting TAK1 phosphorylation and negatively regulating MAPK signaling. These findings can help develop therapeutic strategies to treat and prevent cardiac fibrosis.

Keywords: cardiovascular medicine; cell biology; functional aspects of cell biology; pathophysiology.