Department of Cardiovascular Surgery, Shenzhen People's Hospital, Second Clinical Medical College, Jinan University, Shenzhen, China.
Department of Cardiovascular Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
J Cell Physiol. 2019 Aug;234(10):17749-17756. doi: 10.1002/jcp.28400. Epub 2019 Feb 28.
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.
心肌纤维化是一种以细胞外基质过度沉积为特征的病理生理过程。我们使用横主动脉缩窄（TAC）建立了心肌肥厚模型，以揭示与小鼠心肌细胞细胞外基质过度沉积相关的机制。TAC 导致三结构域蛋白 72（TRIM72）上调，TRIM72 是一种包含三结构域的蛋白质，对增殖和迁移至关重要。重要的是，体内沉默 TRIM72 逆转了 TAC 诱导的心肌纤维化，表现为左心室收缩压明显升高和左心室舒张末期压降低。TRIM72 敲低也减轻了纤维化标志物 I 型胶原和α-平滑肌肌动蛋白（α-SMA）的沉积。在体外研究中，TRIM72 在心脏成纤维细胞中也被类似地上调。TRIM72 敲低显著抑制 I 型胶原和α-SMA 的表达，并显著减少心脏成纤维细胞的增殖和迁移。然而，TRIM72 过表达显著增加 I 型胶原和α-SMA 的表达，并增加心脏成纤维细胞的增殖和迁移。进一步的研究表明，TRIM72 增加了心脏成纤维细胞中磷酸化 STAT3 的表达。心脏成纤维细胞中 TRIM72 的敲低导致 Notch 配体 Jagged-1 及其下游基因和 Notch-1 细胞内结构域的表达增加。Notch-1 的抑制消除了 sh-TRIM72 诱导的心肌纤维化。总之，我们的结果支持 TRIM72 通过调节 STAT3/Notch-1 通路在维持成纤维细胞向肌成纤维细胞转化和抑制成纤维细胞生长中发挥新的作用。
