BNP and connective tissue growth factor interact and co-regulate myocardial fibrosis

• Published in: Journal of cardiac failure Vol. 10; no. 5; p. S179
• Main Authors: Norimichi, Koitabashi, Masashi, Arai, Atai, Watanabe, Kazuo, Niwano, Shirou, Hara, Masahiko, Kurabayashi, Takashi, Nishida, Masaharu, Takigawa
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 01.10.2004
• ISSN: 1071-9164; 1532-8414
• DOI: 10.1016/j.cardfail.2004.08.098

Connective tissue growth factor (CTGF/CCN2/HCS24) is a profibrotic cytokine induced by TGF-beta and promotes proliferation and extracellular matrix production in connective tissues. Recently, up-regulation of CTGF gene in human failing heart has been demonstrated. On the other hand, BNP has been shown to have antifibrotic effects and block the action of TGF-beta. Therefore, we hypothesized that BNP interacts directly with CTGF as well as TGF-beta in cardiac myocytes (CM) and non-myocytes (CNM). Immunohistochemical staining using specific antibody for CTGF revealed that CTGF was produced not only in CNM but also CM. Recombinant CTGF protein markedly increased mRNA expression levels of procollagen type I and type III in CNM. TGF-beta, norepinephrine and angiotensin II increased CTGF mRNA levels in CM. Importantly, overexpression of CTGF mRNA induced by these stimuli was suppressed by the simultaneous administration of recombinant BNP protein in a dose dependent manner. Next, we examined CTGF mRNA expression levels in the rat cardiac hypertrophy model induced by abdominal aortic banding. CTGF mRNA expression levels were elevated in the hypertrophied hearts and the ratio of CTGF mRNA expression against BNP mRNA were significantly correlated with the % area of myocardial fibrosis. In conclusion, our study suggest that CTGF and BNP genes are synergistically regulated under hypertrophic stimuli, even though BNP may counteract the profibrotic process driven by CTGF.