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

Abstract

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 Ⅲ hypertrophy Ⅲ cardiac function Ⅲ connective tissue growth factor Ⅲ natriuretic peptide E pidemiological studies have established that 40% to 50% of patients with heart failure have normal or minimally impaired left ventricular (LV) ejection fraction, a clinical syndrome that is commonly referred to as diastolic heart failure (DHF). These patients typically have cardiac hypertrophy that is induced by long-standing hypertension or by primary hypertrophic cardiomyopathy, as well as increased passive LV stiffness. 1 Among various molecular mechanisms that regulate LV stiffness, 2 abnormalities in the transcriptional or posttranscriptional regulation of the collagen gene can result in the disproportionate accumulation of fibrous tissue and elevation of stiffness in the hypertrophied heart. 2,3 Recent studies have shown that, in addition to mechanical load, autocrine, paracrine, and endocrine factors, such as angiotensin II, aldosterone (Aldo), endothelin-1 (ET1), natriuretic peptides, osteopontin, and transforming growth factor-␤1 (TGF-␤), play important roles in the development of myocardial hypertrophy and fibrosis. 4,5 However, the precise molecular mechanisms that initiate and promote myocardial fibrosis and increases in ventricular stiffness remain largely unknown.Connec...

Association between osteopontin promoter variants and diastolic dysfunction in hypertensive heart in the Japanese population

“…4,7 According to the data from animal model with pressure overload, various biological elements such as neurohumoral factors and growth factors are involved in the pathogenesis of diastolic failure. [8][9][10] In contrast, there are no established mechanisms regarding diastolic failure in hypertensive patients. Thus, further clinical investigation to dissect the mechanism of diastolic failure is required to improve the prognosis of HF with preserved systolic function.…”

The Mineralocorticoid Receptor Promotes Fibrotic Remodeling in Atrial Fibrillation

“…CTGF is a mediator of fibrosis in AF (16,18) and of aldosterone-induced cellular alterations (41,44). Our data demonstrate that aldosterone induces CTGF expression via the MR, whereas cortisol did not.…”

Relation Between Connective Tissue Growth Factor and Cardiac Sympathetic Nerve Activity in Heart Failure in DCM Patients

“…5,6) Koitabashi, et al have previously demonstrated that connective tissue growth factor (CTGF) acts as a mediator of myocardial remodeling and fibrosis. 7,8) Further, CTGF expression is increased in myocardial samples obtained from patients with cardiomyopathy 8) or diastolic heart failure. 7) Transforming growth factor-β (TGF-β) has been demonstrated to mediate cardiac fibrosis as well as fibrosis in other organs.…”

“…7,8) Further, CTGF expression is increased in myocardial samples obtained from patients with cardiomyopathy 8) or diastolic heart failure. 7) Transforming growth factor-β (TGF-β) has been demonstrated to mediate cardiac fibrosis as well as fibrosis in other organs. In addition, it has been shown that the profibrotic effects of TGF-β are partly mediated through induction of CTGF in various organs.…”

“…12,13) In addition, the RAAS activates cardiac sympathetic nerve activity and exacerbates congestive heart failure. 26,27) On the other hand, CTGF induced by angiotensin II causes the hypertrophy of cardiac myocytes, the development of myocardial fibrosis, and cardiac remodeling, 7,8) In this situation, the plasma CTGF level can be strongly related with the condition of the failing heart, in other words, cardiac sympathetic nerve activity. Limitations: This study has several limitations.…”