Premium
TRIM72 contributes to cardiac fibrosis via regulating STAT3/Notch‐1 signaling
Author(s) -
Chen Xu,
Su Jie,
Feng Jianyu,
Cheng Liang,
Li Qing,
Qiu Chen,
Zheng Qijun
Publication year - 2019
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.28400
Subject(s) - gene knockdown , cardiac fibrosis , downregulation and upregulation , extracellular matrix , fibroblast , fibrosis , notch signaling pathway , myofibroblast , microbiology and biotechnology , myocardial fibrosis , ctgf , biology , chemistry , cancer research , endocrinology , medicine , signal transduction , cell culture , in vitro , growth factor , receptor , biochemistry , genetics , gene
Cardiac fibrosis is a pathophysiological process characterized by excessive deposition of extracellular matrix. We developed a cardiac hypertrophy model using transverse aortic constriction (TAC) to uncover mechanisms relevant to excessive deposition of extracellular matrix in mouse myocardial cells. TAC caused upregulation of Tripartite motif protein 72 (TRIM72), a tripartite motif‐containing protein that is critical for proliferation and migration. Importantly, in vivo silencing of TRIM72 reversed TAC‐induced cardiac fibrosis, as indicated by markedly increased left ventricular systolic pressure and decreased left ventricular end‐diastolic pressure. TRIM72 knockdown also attenuated deposition of fibrosis marker collagen type I and α‐smooth muscle actin (α‐SMA). In an in vitro study, TRIM72 was similarly upregulated in cardiac fibroblasts. Knockdown of TRIM72 markedly suppressed collagen type I and α‐SMA expression and significantly decreased the proliferation and migration of cardiac fibroblasts. However, TRIM72 overexpression markedly increased collagen type I and α‐SMA expression and increased the proliferation and migration of cardiac fibroblasts. Further study demonstrated that TRIM72 increased phosphorylated STAT3 in cardiac fibroblasts. TRIM72 knockdown in cardiac fibroblasts resulted in increased expression of Notch ligand Jagged‐1 and its downstream gene and Notch‐1 intracellular domain. Inhibition of Notch‐1 abrogated sh‐TRIM72‐induced cardiac fibrosis. Together, our results support a novel role for TRIM72 in maintaining fibroblast‐to‐myofibroblast transition and suppressing fibroblast growth by regulating the STAT3/Notch‐1 pathway.