Regulation of connective tissue growth factor gene expression and fibrosis in human heart failure Journal Article


Authors: Koshman, Y. E.; Patel, N; Chu, M.; Iyengar, R.; Kim, T.; Ersahin, C.; Lewis, W.; Heroux, A.; Samarel, A. M.
Article 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. METHODS AND 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) beta1, collagen (COL) 1-alpha1, COL3-alpha1, matrix metalloproteinase (MMP) 2, and MMP9 mRNA in ICM and DCM were also significantly elevated compared with NF samples. Although TGF-beta1, CTGF, COL1-alpha1, and COL3-alpha1 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.
Keywords: Department of Medicine
Journal Title: Journal of cardiac failure
Volume: 19
Issue: 4
ISSN: 1532-8414; 1071-9164
Publisher: Elsevier Inc  
Journal Place: United States
Date Published: 2013
Start Page: 283
End Page: 294
Language: eng
DOI/URL:
Notes: ID: 12924; CI: Copyright (c) 2013; GR: P01 HL062426/HL/NHLBI NIH HHS/United States; JID: 9442138; NIHMS461180; OID: NLM: NIHMS461180 [Available on 04/01/14]; OID: NLM: PMC3643143 [Available on 04/01/14]; PMCR: 2014/04/01 00:00; 2012/05/23 [received]; 2012/12/26 [revised]; 2013/01/28 [accepted]; 2013/03/19 [aheadofprint]; ppublish