CTRP3 attenuates post-infarct cardiac fibrosis by targeting Smad3 activation and inhibiting myofibroblast differentiation
CTRP3 attenuates post-infarct cardiac fibrosis by targeting Smad3 activation and inhibiting myofibroblast differentiation
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CTRP3 通过靶向 Smad3 激活和抑制肌成纤维细胞分化来减轻梗死后心脏纤维化
DOI：
10.1007/s00109-015-1309-8
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发表时间：
2015-12-01
影响因子：
4.7
通讯作者：
Wu, Li-Ling
中科院分区：
文献类型：
--
作者：
Wu, Dan;Lei, Hong;Wu, Li-Ling
C1q/肿瘤坏死因子相关蛋白-3(CTRP3)是一种新的脂肪因子，对代谢、炎症和心血管系统具有调节作用。本研究旨在探讨CTRP3对心肌纤维化的影响及其机制。心肌梗死(MI)后心肌CTRP3表达明显降低。腺病毒介导的CTRP3补充剂可减轻心肌肥厚，改善心功能，抑制间质纤维化，减少心肌梗死后肌成纤维细胞的数量。在培养的成年大鼠心脏成纤维细胞(CFs)中，CTRP3抑制转化生长因子-β1诱导的细胞增殖和迁移，抑制结缔组织生长因子、I型和III型胶原的表达。此外，CTRP3抑制转化生长因子-β1诱导的α-SMA和促纤维化分子的表达，而CTRP3促进α-SMA和促纤维化分子的表达。CTRP3还抑制转化生长因子-β1诱导的Smad3的磷酸化、核转位和与p300的相互作用。CTRP3使大鼠心脏和CFs中AMPK和Akt的磷酸化水平升高。AMPK抑制剂9-β-d-阿拉伯呋喃诺苷(Araa)可阻断CTRP3对转化生长因子-β1诱导的纤维化反应和Smad3活化的保护作用。综上所述，CTRP3通过抑制肌成纤维细胞分化和随后细胞外基质的产生来减轻心脏纤维化。CTRP3通过靶向Smad3激活和抑制肌成纤维细胞分化发挥抗纤维化作用。CTRP3减轻心肌梗死后大鼠模型和心脏成纤维细胞的纤维化。CTRP3抑制成纤维细胞向肌成纤维细胞分化。CTRP3通过靶向Smad3激活发挥抗纤维化作用。AMPK通过抑制Smad3激活介导CTRP3的抗纤维化作用。
C1q/tumor necrosis factor-related protein-3 (CTRP3) is a novel adipokine with modulation effects on metabolism, inflammation, and cardiovascular system. This study aimed to investigate the effect of CTRP3 on cardiac fibrosis and its underlying mechanism. The myocardial expression of CTRP3 was significantly decreased after myocardial infarction (MI). Adenovirus-delivered CTRP3 supplement attenuated myocardial hypertrophy, improved cardiac function, inhibited interstitial fibrosis, and decreased the number of myofibroblasts post-MI. In cultured adult rat cardiac fibroblasts (CFs), CTRP3 attenuated cell proliferation; migration; and the expression of connective tissue growth factor, collagen I, and collagen III induced by transforming growth factor (TGF)-beta 1. Moreover, CTRP3 inhibited whereas CTRP3 small interfering RNA (siRNA) facilitated the expression of alpha-SMA and profibrotic molecules induced by TGF-beta 1. CTRP3 also attenuated TGF-beta 1-induced Smad3 phosphorylation, nuclear translocation, and interaction with p300. CTRP3 increased the phosphorylation of AMP-activated protein kinase (AMPK) and Akt in both rat hearts and CFs. Adenine 9-beta-d-arabinofuranoside (AraA), an AMPK inhibitor, abolished the protective effect of CTRP3 against TGF-beta 1-induced profibrotic response and Smad3 activation. Taken together, CTRP3 attenuates cardiac fibrosis by inhibiting myofibroblast differentiation and the subsequent extracellular matrix production. AMPK is required for the anti-fibrotic effect of CTRP3 through targeting Smad3 activation and inhibiting myofibroblast differentiation.CTRP3 alleviates cardiac fibrosis in a rat post-MI model and in cardiac fibroblasts.CTRP3 inhibits fibroblast-to-myofibroblast differentiation.CTRP3 exerts anti-fibrotic effect through targeting Smad3 activation.AMPK mediates the anti-fibrotic effect of CTRP3 by inhibition of Smad3 activation.