Increased connective tissue growth factor relative to brain natriuretic peptide as a determinant of myocardial fibrosis.
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-beta 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.
Koitabashi
Norimichi
N
Department of Medicine and Biological Science, Gunma University Graduate School of Medicine, Japan.
Arai
Masashi
M
Kogure
Shinya
S
Niwano
Kazuo
K
Watanabe
Atai
A
Aoki
Yasuhiro
Y
Maeno
Toshitaka
T
Nishida
Takashi
T
Kubota
Satoshi
S
Takigawa
Masaharu
M
Kurabayashi
Masahiko
M
D000368:Aged; D000818:Animals; D006332:Cardiomegaly / Q000150:complications / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D002478:Cells, Cultured; D055513:Connective Tissue Growth Factor; D004548:Elasticity; D004719:Endomyocardial Fibrosis / Q000378:metabolism* / Q000473:pathology*; D005355:Fibrosis; D015870:Gene Expression; D006801:Humans; D017874:Immediate-Early Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism; D020097:Natriuretic Peptide, Brain / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D055514:Nephroblastoma Overexpressed Protein; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013268:Stimulation, Chemical; D013318:Stroke Volume; D014158:Transcription, Genetic; D018754:Ventricular Dysfunction / Q000209:etiology
C526317:CCN2 protein, human; C526316:CCN2 protein, rat; C526319:CCN3 protein, human; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D055514:Nephroblastoma Overexpressed Protein; D012333:RNA, Messenger; D020097:Natriuretic Peptide, Brain; D055513:Connective Tissue Growth Factor