摘要：SummaryThe 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 vitrooverexpression 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.Graphical abstractDisplay OmittedHighlights•TRIM38 expression is negatively correlated with cardiac fibrosis progression•TRIM38 ameliorates the proliferation and secretion of CFs post fibrotic stimulation•TRIM38 overexpression attenuates cardiac fibrosis progression in MI mice•TRIM38 inhibits the TAK1/MAPK pathway by targeting the degradation of TAB2 and TAB3Cardiovascular medicine; Pathophysiology; Cell biology; Functional aspects of cell biology
