TRIM72 contributes to cardiac fibrosis via regulating STAT3/Notch‐1 signaling

Abstract

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.

Adipose mesenchymal stem cell transplantation alleviates spinal cord injury-induced neuroinflammation partly by suppressing the Jagged1/Notch pathway

“…The activation of STAT3 via phosphorylation by Janus kinases (JAKs) has been demonstrated in a variety of disease models, including models of Alzheimer's and Huntington's diseases [29], cerebral ischemia [30], and SCI [31]. A large number of studies have indicated a strong association between Notch and JAK/STAT3 signaling, and a change in Notch expression can alter STAT3 phosphorylation and activity [32][33][34]. However, whether JAK/STAT3 signaling participates in the suppressive effects of MSCs on Notch1 expression after SCI is still unclear.…”

Blocking Notch signal pathway suppresses the activation of neurotoxic A1 astrocytes after spinal cord injury

“…Numerous studies have demonstrated a strong association between Notch and Stat3 signaling. Notably, a change in Notch expression can alter Stat3 phosphorylation and activity [28,35,36], suggesting that Notch signaling can alter astrocyte phenotype by affecting Stat3 activity and function.…”

Integrated Analysis of Immunocyte Infiltration and Differential Gene Expression in Hypertrophic Obstructive Cardiomyopathy

“…STAT3 has a key role in in ammation that underlies cardiovascular disease and impacts on cardiac structure and function and is important for maintaining endothelial cell function and capillary integrity with aging and hypertension [32]. Besides, STAT3 also involves the cardiac hypertrophy and brosis in TAC mouse models [33,34]. Duerr GD et al suggested that in the cardiac hypertrophy group CCL2 and CXCL8 had increased expression and anti-in ammatory IL-10 had a suppression which indicated the persistent in ammatory reaction [35].…”