title: Matricellular Protein CCN5 Reverses Established Cardiac Fibrosis.
abstract: Cardiac fibrosis (CF) is associated with increased ventricular stiffness and diastolic dysfunction and is an independent predictor of long-term clinical outcomes of patients with heart failure (HF). We previously showed that the matricellular CCN5 protein is cardioprotective via its ability to inhibit CF and preserve cardiac contractility.
  
  
  
  This study examined the role of CCN5 in human heart failure and tested whether CCN5 can reverse established CF in an experimental model of HF induced by pressure overload.
  
  
  
  Human hearts were obtained from patients with end-stage heart failure. Extensive CF was induced by applying transverse aortic constriction for 8 weeks, which was followed by adeno-associated virus-mediated transfer of CCN5 to the heart. Eight weeks following gene transfer, cellular and molecular effects were examined.
  
  
  
  Expression of CCN5 was significantly decreased in failing hearts from patients with end-stage heart failure compared to nonfailing hearts. Trichrome staining and myofibroblast content measurements revealed that the established CF had been reversed by CCN5 gene transfer. Anti-CF effects of CCN5 were associated with inhibition of the transforming growth factor beta signaling pathway. CCN5 significantly inhibited endothelial-mesenchymal transition and fibroblast-to-myofibroblast transdifferentiation, which are 2 critical processes for CF progression, both in vivo and in vitro. In addition, CCN5 induced apoptosis in myofibroblasts, but not in cardiomyocytes or fibroblasts, both in vivo and in vitro. CCN5 provoked the intrinsic apoptotic pathway specifically in myofibroblasts, which may have been due the ability of CCN5 to inhibit the activity of NFκB, an antiapoptotic molecule.
  
  
  
  CCN5 can reverse established CF by inhibiting the generation of and enhancing apoptosis of myofibroblasts in the myocardium. CCN5 may provide a novel platform for the development of targeted anti-CF therapies.
authors.affiliation: Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Dongtak
authors.initials: D
authors.lastname: Jeong
authors.affiliation: School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, South Korea.
authors.forename: Min-Ah
authors.initials: MA
authors.lastname: Lee
authors.affiliation: School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, South Korea.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Dong Kwon
authors.initials: DK
authors.lastname: Yang
authors.affiliation: Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Changwon
authors.initials: C
authors.lastname: Kho
authors.affiliation: Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Jae Gyun
authors.initials: JG
authors.lastname: Oh
authors.affiliation: School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, South Korea.
authors.forename: Gyeongdeok
authors.initials: G
authors.lastname: Hong
authors.affiliation: Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Ahyoung
authors.initials: A
authors.lastname: Lee
authors.affiliation: School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, South Korea.
authors.forename: Min Ho
authors.initials: MH
authors.lastname: Song
authors.affiliation: Benioff Children's Hospital, University of California, San Francisco, California.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: LaRocca
authors.affiliation: Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Jiqiu
authors.initials: J
authors.lastname: Chen
authors.affiliation: Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Lifan
authors.initials: L
authors.lastname: Liang
authors.affiliation: Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Mitsuyama
authors.affiliation: Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Valentina
authors.initials: V
authors.lastname: D'Escamard
authors.affiliation: Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Jason C
authors.initials: JC
authors.lastname: Kovacic
authors.affiliation: Paean Biotechnology, Chungnam National University, Daejeon, Korea.
authors.forename: Tae Hwan
authors.initials: TH
authors.lastname: Kwak
authors.affiliation: Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Hajjar
authors.affiliation: School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, South Korea. Electronic address: woojinpark@icloud.com.
authors.forename: Woo Jin
authors.initials: WJ
authors.lastname: Park
mesh_terms: D000818:Animals; D017209:Apoptosis; D055511:CCN Intercellular Signaling Proteins / Q000235:genetics / Q000378:metabolism*; D054338:Cell Transdifferentiation; D000229:Dependovirus; D015536:Down-Regulation; D058750:Epithelial-Mesenchymal Transition; D005355:Fibrosis; D015316:Genetic Therapy; D005822:Genetic Vectors; D006333:Heart Failure / Q000378:metabolism; D006801:Humans; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D058628:Myofibroblasts / Q000473:pathology; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D055511:CCN Intercellular Signaling Proteins; C413323:CCN5 protein, human; D012097:Repressor Proteins; D016212:Transforming Growth Factor beta
keywords: NFκB; apoptosis; gene therapy; heart failure