Published Online
on March 19, 2007

A more recent version of this article appeared on May 1, 2007

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Submitted on July 24, 2006
Revised on August 13, 2006

Increased Connective Tissue Growth Factor Relative to Brain Natriuretic Peptide as a Determinant of Myocardial Fibrosis

Norimichi Koitabashi; Masashi Arai^*; Shinya Kogure; Kazuo Niwano; Atai Watanabe; Yasuhiro Aoki; Toshitaka Maeno; Takashi Nishida; Satoshi Kubota; Masaharu Takigawa; and Masahiko Kurabayashi

From the Department of Medicine and Biological Science (N.K., M.A., S.K., K.N., A.W., Y.A., T.M., M.K.), Gunma University Graduate School of Medicine, Gunma, Japan; and the Department of Biochemistry and Molecular Dentistry (T.N., S.K., M.T.), Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.

^* To whom correspondence should be addressed. E-mail: araim{at}showa.gunma-u.ac.jp.

Abstract--Excessive fibrosis contributes to an increase in left ventricular stiffness. The goal of the present study was to investigate the role of connective tissue growth factor (CCN2/CTGF), a profibrotic cytokine of the CCN (Cyr61, CTGF, and Nov) family, and its functional interactions with brain natriuretic peptide (BNP), an antifibrotic peptide, in the development of myocardial fibrosis and diastolic heart failure. Histological examination on endomyocardial biopsy samples from patients without systolic dysfunction revealed that the abundance of CTGF-immunopositive cardiac myocytes was correlated with the excessive interstitial fibrosis and a clinical history of acute pulmonary congestion. In a rat pressure overload cardiac hypertrophy model, CTGF mRNA levels and BNP mRNA were increased in proportion to one another in the myocardium. Interestingly, relative abundance of mRNA for CTGF compared with BNP was positively correlated with diastolic dysfunction, myocardial fibrosis area, and procollagen type 1 mRNA expression. Investigation with conditioned medium and subsequent neutralization experiments using primary cultured cells demonstrated that CTGF secreted by cardiac myocytes induced collagen production in cardiac fibroblasts. Further, G protein-coupled receptor ligands induced expression of the CTGF and BNP genes in cardiac myocytes, whereas aldosterone and transforming growth factor- preferentially induced expression of the CTGF gene. Finally, exogenous BNP prevented the production of CTGF in cardiac myocytes. These data suggest that a disproportionate increase in CTGF relative to BNP in cardiac myocytes plays a central role in the induction of excessive myocardial fibrosis and diastolic heart failure.

Key words: extracellular matrix • hypertrophy • cardiac function • connective tissue growth factor • natriuretic peptide

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