title: CTRP3 attenuates post-infarct cardiac fibrosis by targeting Smad3 activation and inhibiting myofibroblast differentiation.
abstract: 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)-β1. Moreover, CTRP3 inhibited whereas CTRP3 small interfering RNA (siRNA) facilitated the expression of α-SMA and profibrotic molecules induced by TGF-β1. CTRP3 also attenuated TGF-β1-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-β-D-arabinofuranoside (AraA), an AMPK inhibitor, abolished the protective effect of CTRP3 against TGF-β1-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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Physiology and Pathophysiology, Peking University Health Science Center, and Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, 100191, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Wu
authors.affiliation: Department of Physiology and Pathophysiology, Peking University Health Science Center, and Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, 100191, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Lei
authors.affiliation: Department of Physiology and Pathophysiology, Peking University Health Science Center, and Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, 100191, China.
authors.forename: Jin-Yu
authors.initials: JY
authors.lastname: Wang
authors.affiliation: Department of Physiology and Pathophysiology, Peking University Health Science Center, and Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, 100191, China.
authors.forename: Cheng-Lin
authors.initials: CL
authors.lastname: Zhang
authors.affiliation: Department of Physiology and Pathophysiology, Peking University Health Science Center, and Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, 100191, China.
authors.forename: Han
authors.initials: H
authors.lastname: Feng
authors.affiliation: Department of Physiology and Pathophysiology, Peking University Health Science Center, and Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, 100191, China.
authors.forename: Feng-Ying
authors.initials: FY
authors.lastname: Fu
authors.affiliation: Department of Physiology and Pathophysiology, Peking University Health Science Center, and Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, 100191, China. lilyby@163.com.
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Physiology and Pathophysiology, Peking University Health Science Center, and Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, 100191, China. pathophy@bjmu.edu.cn.
authors.forename: Li-Ling
authors.initials: LL
authors.lastname: Wu
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000256:Adenoviridae / Q000235:genetics; D054392:Adipokines / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D006332:Cardiomegaly / Q000209:etiology / Q000503:physiopathology; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D004195:Disease Models, Animal; D050881:E1A-Associated p300 Protein / Q000378:metabolism; D005355:Fibrosis; D015870:Gene Expression; D005786:Gene Expression Regulation / Q000187:drug effects; D055785:Gene Knockdown Techniques; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D008297:Male; D009203:Myocardial Infarction / Q000150:complications / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D058628:Myofibroblasts / Q000166:cytology* / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D021381:Protein Transport; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D051900:Smad3 Protein / Q000378:metabolism*; D014161:Transduction, Genetic; D053773:Transforming Growth Factor beta1 / Q000378:metabolism / Q000494:pharmacology; D020257:Ventricular Remodeling / Q000235:genetics
chemical_list: D054392:Adipokines; C000590534:C1q tumor necrosis factor-related protein 3, rat; D051900:Smad3 Protein; D053773:Transforming Growth Factor beta1; D050881:E1A-Associated p300 Protein; D051057:Proto-Oncogene Proteins c-akt; D055372:AMP-Activated Protein Kinases
keywords: C1q/tumor necrosis factor-related protein-3 (CTRP3); Cardiac fibrosis; Myocardial infarction (MI); Myofibroblast differentiation; Smad3