C1q/tumor necrosis factor-related protein-6 attenuates post-infarct cardiac fibrosis by targeting RhoA/MRTF-A pathway and inhibiting myofibroblast differentiation
C1q/tumor necrosis factor-related protein-6 attenuates post-infarct cardiac fibrosis by targeting RhoA/MRTF-A pathway and inhibiting myofibroblast differentiation
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C1q/肿瘤坏死因子相关蛋白 6 通过靶向 RhoA/MRTF-A 通路并抑制肌成纤维细胞分化来减轻梗死后心脏纤维化
DOI：
10.1007/s00395-015-0492-7
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发表时间：
2015-07-01
影响因子：
9.5
通讯作者：
Wu, Li-Ling
中科院分区：
文献类型：
--
作者：
Lei, Hong;Wu, Dan;Wu, Li-Ling
C1 q/肿瘤坏死因子相关蛋白-6（CTRP 6）是新近发现的一种脂联素蛋白，具有调节代谢和炎症的作用。然而，CTRP 6的心血管功能仍然未知。本研究旨在明确其在心肌纤维化中的作用并探讨其可能的机制。采用结扎大鼠冠状动脉左前降支的方法制备心肌梗死模型。CTRP 6主要表达于成年大鼠心肌细胞的胞浆中，在MI后的边缘区和梗死区表达显著减少。腺病毒介导的CTRP 6递送改善了心脏功能，减轻了心脏肥大，减轻了心脏纤维化，并抑制了心肌成纤维细胞分化以及MI后胶原蛋白I、胶原蛋白III和结缔组织生长因子的表达。在培养的成年大鼠心脏成纤维细胞（CFs）中，外源性或心肌细胞分泌的CTRP 6抑制，而CTRP 6的敲低促进转化生长因子-β 1（TGF-β 1）诱导的α-平滑肌肌动蛋白，平滑肌22 α和促纤维化分子的表达。CTRP 6对CFs增殖无影响，但减弱TGF-β 1诱导的CFs迁移。CTRP 6增加CF和MI后心脏中AMP活化蛋白激酶（AMPK）和Akt的磷酸化。AMPK抑制剂腺嘌呤9-β-D-阿拉伯呋喃糖苷（AraA）或磷脂酰肌醇-3-激酶（PI 3 K）抑制剂LY 294002预处理可消除CTRP 6对TGF-β 1诱导的促纤维化反应的保护作用。CTRP 6对TGF-β 1诱导的Smad 3磷酸化和核转位无影响，但显著降低TGF-β 1诱导的RhoA活化和心肌素相关转录因子-A（MRTF-A）核转位，这些作用可被AMPK或Akt抑制剂阻断。总之，CTRP 6通过抑制肌成纤维细胞分化来减弱心脏纤维化。AMPK和Akt激活通过靶向RhoA/MRTF-A通路负责CTRP 6介导的抗纤维化作用。
C1q/tumor necrosis factor-related protein-6 (CTRP6) is a newly identified adiponectin paralog with modulation effects on metabolism and inflammation. However, the cardiovascular function of CTRP6 remains unknown. This study aimed to determine its role in cardiac fibrosis and explore the possible mechanism. Myocardial infarction (MI) was induced by left anterior descending coronary artery ligation in rats. CTRP6 was mainly expressed in the cytoplasm of adult rat cardiomyocytes and significantly decreased in the border and infarct zones post-MI. Adenovirus-mediated CTRP6 delivery improved cardiac function, attenuated cardiac hypertrophy, alleviated cardiac fibrosis, and inhibited myofibroblast differentiation as well as the expression of collagen I, collagen III, and connective tissue growth factor post-MI. In cultured adult rat cardiac fibroblasts (CFs), exogenous or cardiomyocyte-secreted CTRP6 inhibited, whereas knockdown of CTRP6 facilitated transforming growth factor-beta 1 (TGF-beta 1)-induced expression of alpha-smooth muscle actin, smooth muscle 22 alpha, and profibrotic molecules. CTRP6 had no effect on CFs proliferation but attenuated CFs migration induced by TGF-beta 1. CTRP6 increased the phosphorylation of AMP-activated protein kinase (AMPK) and Akt in CFs and post-MI hearts. Pretreatment with adenine 9-beta-D-arabinofuranoside (AraA), an AMPK inhibitor, or LY294002, a phosphatidylinositol-3-kinase (PI3 K) inhibitor, abolished the protective effect of CTRP6 on TGF-beta 1-induced profibrotic response. Furthermore, CTRP6 had no effect on TGF-beta 1-induced Smad3 phosphorylation and nuclear translocation, whereas significantly decreased TGF-beta 1-induced RhoA activation and myocardin-related transcription factor-A (MRTF-A) nuclear translocation, and these effects were blocked by AMPK or Akt inhibition. In conclusion, CTRP6 attenuates cardiac fibrosis via inhibiting myofibroblast differentiation. AMPK and Akt activation are responsible for the CTRP6-mediated anti-fibrotic effect by targeting RhoA/MRTF-A pathway.