CTRP15 derived from cardiac myocytes attenuates TGFβ1-induced fibrotic response in cardiac fibroblasts
CTRP15 derived from cardiac myocytes attenuates TGFβ1-induced fibrotic response in cardiac fibroblasts
复制标题
源自心肌细胞的 CTRP15 可减弱 TGF beta 1 诱导的心脏成纤维细胞纤维化反应
DOI：
10.1007/s10557-020-06970-6
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发表时间：
2020-05-19
影响因子：
3.4
通讯作者：
Li, Li
中科院分区：
文献类型：
--
作者：
Zhao, Qian;Zhang, Cheng-Lin;Li, Li
目的心脏纤维化是以细胞外基质(ECM)成分在心肌中的净积聚为特征，并促进心力衰竭的发展。C1q/肿瘤坏死因子相关蛋白15(CTRP15)是CTRP家族的新成员，其基因在成年小鼠心脏中表达。本研究旨在探讨CTRP15在压力超负荷诱导的纤维化重塑中的作用。方法采用小鼠横断主动脉缩窄(TAC)模型，将携带CTRP15基因的9型腺相关病毒(AAV9)注射到小鼠体内，实现CTRP15在心肌中的高表达。将携带CTRP15或小干扰RNA(SiRNA)基因的腺病毒感染培养的新生小鼠心肌细胞(NMVCs)或心肌成纤维细胞(CFs)。实时定量聚合酶链式反应检测基因表达，免疫印迹、免疫细胞化学和免疫荧光染色检测蛋白表达和分布。结果CTRP15主要由心肌细胞产生。在接受TAC的小鼠中，左心室CTRP15的表达下调。AAV9介导的CTRP15过表达减轻了压力超负荷小鼠的心室重构和功能障碍。用重组CTRP15或含CTRP15的条件培养液处理CFs可抑制转化生长因子-β1诱导的Smad3活化和肌成纤维细胞分化。CTRP15增加胰岛素受体(IR)、胰岛素受体底物-1(IRS-1)和Akt的磷酸化。阻断IR/IRS-1/Akt通路可逆转CTRP15对转化生长因子-β1诱导的Smad3激活的抑制作用。结论CTRP15对压力超负荷所致心脏重构具有抗纤维化作用。IR/IRS-1/Akt通路的激活通过靶向Smad3参与了CTRP15的抗纤维化作用。
Purpose Cardiac fibrosis is characterized by net accumulation of extracellular matrix (ECM) components in the myocardium and facilitates the development of heart failure. C1q/tumor necrosis factor-related protein 15 (CTRP15) is a novel member of the CTRP family, and its gene expression is detected in adult mouse hearts. The present study was performed to determine the effect of CTRP15 on pressure overload-induced fibrotic remodeling. Methods Mice were subjected to transverse aortic constriction (TAC) surgery, and adeno-associated virus serotype 9 (AAV9)-carrying mouse CTRP15 gene was injected into mice to achieve CTRP15 overexpression in the myocardium. Adenovirus carrying the gene encoding CTRP15 or small interfering RNA (siRNA) of interest was infected into cultured neonatal mouse ventricular cardiomyocytes (NMVCs) or cardiac fibroblasts (CFs). Gene expression was measured by quantitative real-time PCR, and protein expression and distribution were determined by Western blotting, immunocytochemistry, and immunofluorescence staining. Results CTRP15 was predominantly produced by cardiac myocytes. CTRP15 expression in the left ventricles was downregulated in mice that underwent TAC. AAV9-mediated CTRP15 overexpression alleviated ventricular remodeling and dysfunction in the pressure-overloaded mice. Treatment of CFs with recombinant CTRP15 or the conditioned medium containing CTRP15 inhibited transforming growth factor (TGF)-beta 1-induced Smad3 activation and myofibroblast differentiation. CTRP15 increased phosphorylation of insulin receptor (IR), insulin receptor substrate-1 (IRS-1), and Akt. Blockade of IR/IRS-1/Akt pathway reversed the inhibitory effect of CTRP15 on TGF-beta 1-induced Smad3 activation. Conclusion CTRP15 exerts an anti-fibrotic effect on pressure overload-induced cardiac remodeling. The activation of IR/IRS-1/Akt pathway contributes to the anti-fibrotic effect of CTRP15 through targeting Smad3.