title: Regulation of connective tissue growth factor gene expression and fibrosis in human heart failure.
abstract: BACKGROUND
  Heart failure (HF) is associated with excessive extracellular matrix (ECM) deposition and abnormal ECM degradation leading to cardiac fibrosis. Connective tissue growth factor (CTGF) modulates ECM production during inflammatory tissue injury, but available data on CTGF gene expression in failing human heart and its response to mechanical unloading are limited.
  
  
  RESULTS
  Left ventricle (LV) tissue from patients undergoing cardiac transplantation for ischemic (ICM; n = 20) and dilated (DCM; n = 20) cardiomyopathies and from nonfailing (NF; n = 20) donor hearts were examined. Paired samples (n = 15) from patients undergoing LV assist device (LVAD) implantation as "bridge to transplant" (34-1,145 days) also were analyzed. There was more interstitial fibrosis in both ICM and DCM compared with NF hearts. Hydroxyproline concentration was also significantly increased in DCM compared with NF samples. The expression of CTGF, transforming growth factor (TGF) β1, collagen (COL) 1-α1, COL3-α1, matrix metalloproteinase (MMP) 2, and MMP9 mRNA in ICM and DCM were also significantly elevated compared with NF samples. Although TGF-β1, CTGF, COL1-α1, and COL3-α1 mRNA levels were reduced by unloading, there was only a modest reduction in tissue fibrosis and no difference in protein-bound hydroxyproline concentration between pre- and post-LVAD tissue samples. The persistent fibrosis may be related to a concomitant reduction in MMP9 mRNA and protein levels following unloading.
  
  
  CONCLUSIONS
  CTGF may be a key regulator of fibrosis during maladaptive remodeling and progression to HF. Although mechanical unloading normalizes most genotypic and functional abnormalities, its effect on ECM remodeling during HF is incomplete.
authors.affiliation: Department of Medicine, Stritch School of Medicine, Loyola University Chicago, Maywood, IL, USA.
authors.forename: Yevgeniya E
authors.initials: YE
authors.lastname: Koshman
authors.forename: Nilamkumar
authors.initials: N
authors.lastname: Patel
authors.forename: Miensheng
authors.initials: M
authors.lastname: Chu
authors.forename: Rekha
authors.initials: R
authors.lastname: Iyengar
authors.forename: Taehoon
authors.initials: T
authors.lastname: Kim
authors.forename: Cagatay
authors.initials: C
authors.lastname: Ersahin
authors.forename: William
authors.initials: W
authors.lastname: Lewis
authors.forename: Alain
authors.initials: A
authors.lastname: Heroux
authors.forename: Allen M
authors.initials: AM
authors.lastname: Samarel
mesh_terms: D002311:Cardiomyopathy, Dilated / Q000175:diagnosis / Q000378:metabolism / Q000473:pathology*; D055513:Connective Tissue Growth Factor / Q000096:biosynthesis* / Q000235:genetics; D005355:Fibrosis; D005786:Gene Expression Regulation; D006333:Heart Failure / Q000175:diagnosis / Q000378:metabolism* / Q000473:pathology*; D016027:Heart Transplantation / Q000639:trends; D006801:Humans; D020257:Ventricular Remodeling / Q000235:genetics
chemical_list: C526317:CCN2 protein, human; D055513:Connective Tissue Growth Factor