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, Masahiko Kurabayashi

Research output: Contribution to journalArticle

105 Citations (Scopus)

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-β 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.

Original languageEnglish
Pages (from-to)1120-1127
Number of pages8
JournalHypertension
Volume49
Issue number5
DOIs
Publication statusPublished - May 2007

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Connective Tissue Growth Factor
Brain Natriuretic Peptide
Cardiac Myocytes
Fibrosis
Diastolic Heart Failure
Messenger RNA
Cardiomegaly
Transforming Growth Factors
Conditioned Culture Medium
G-Protein-Coupled Receptors
Collagen Type I
Aldosterone
Cultured Cells
Myocardium
Collagen
Fibroblasts
Cytokines
Ligands
Biopsy
Gene Expression

Keywords

  • Cardiac function
  • Connective tissue growth factor
  • Extracellular matrix
  • Hypertrophy
  • Natriuretic peptide

ASJC Scopus subject areas

  • Internal Medicine

Cite this

Koitabashi, N., Arai, M., Kogure, S., Niwano, K., Watanabe, A., Aoki, Y., ... Kurabayashi, M. (2007). Increased connective tissue growth factor relative to brain natriuretic peptide as a determinant of myocardial fibrosis. Hypertension, 49(5), 1120-1127. https://doi.org/10.1161/HYPERTENSIONAHA.106.077537

Increased connective tissue growth factor relative to brain natriuretic peptide as a determinant of myocardial fibrosis. / Koitabashi, Norimichi; Arai, Masashi; Kogure, Shinya; Niwano, Kazuo; Watanabe, Atai; Aoki, Yasuhiro; Maeno, Toshitaka; Nishida, Takashi; Kubota, Satoshi; Takigawa, Masaharu; Kurabayashi, Masahiko.

In: Hypertension, Vol. 49, No. 5, 05.2007, p. 1120-1127.

Research output: Contribution to journalArticle

Koitabashi, Norimichi ; Arai, Masashi ; Kogure, Shinya ; Niwano, Kazuo ; Watanabe, Atai ; Aoki, Yasuhiro ; Maeno, Toshitaka ; Nishida, Takashi ; Kubota, Satoshi ; Takigawa, Masaharu ; Kurabayashi, Masahiko. / Increased connective tissue growth factor relative to brain natriuretic peptide as a determinant of myocardial fibrosis. In: Hypertension. 2007 ; Vol. 49, No. 5. pp. 1120-1127.
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