Increased connective tissue growth factor relative to brain natriuretic peptide as a determinant of myocardial fibrosis
Increased connective tissue growth factor relative to brain natriuretic peptide as a determinant of myocardial fibrosis
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DOI：
10.1161/hypertensionaha.106.077537
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发表时间：
2007-05-01
期刊：
影响因子：
8.3
通讯作者：
Kurabayashi, Masahiko
中科院分区：
文献类型：
--
作者：
Koitabashi, Norimichi;Arai, Masashi;Kurabayashi, Masahiko
过度的纤维化导致左心室僵硬的增加。本研究的目的是探讨结缔组织生长因子(CCN2/CTGF)在心肌纤维化和舒张性心力衰竭中的作用。结缔组织生长因子是CCN(Cyr61、CTGF和Nov)家族中的一种促纤维化细胞因子，它与抗纤维化多肽脑利钠肽(BNP)的功能相互作用。对无收缩功能障碍患者心内膜心肌活检标本的组织学检查显示，CTGF免疫阳性心肌细胞的丰富与间质过度纤维化和急性肺充血的临床病史有关。在大鼠压力负荷性心肌肥厚模型中，心肌CTGF mRNA和BNP mRNA水平呈比例升高。有趣的是，与BNP相比，CTGF的相对丰度与舒张期功能不全、心肌纤维化面积和1型前胶原mRNA的表达呈正相关。条件培养液的研究和原代培养细胞的中和实验表明，心肌细胞分泌的CTGF可诱导心脏成纤维细胞产生胶原。此外，G蛋白偶联受体配体诱导心肌细胞CTGF和BNP基因表达，而醛固酮和转化生长因子-β优先诱导CTGF基因表达。最后，外源性BNP可抑制心肌细胞CTGF的产生。这些数据表明，心肌细胞中CTGF相对于BNP的不成比例的增加在诱导过度的心肌纤维化和舒张性心力衰竭中起着核心作用。
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.