CTGF expression is induced by TGF-β in cardiac fibroblasts and cardiac myocytes:: a potential role in heart fibrosis
CTGF expression is induced by TGF-β in cardiac fibroblasts and cardiac myocytes:: a potential role in heart fibrosis
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DOI：
10.1006/jmcc.2000.1215
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发表时间：
2000-10-01
影响因子：
5
通讯作者：
Joly, AH
中科院分区：
文献类型：
--
作者：
Chen, MM;Lam, A;Joly, AH
结缔组织生长因子（CTGF）是由转化生长因子β (tgf - β)在结缔组织细胞中诱导产生的一种富含半胱氨酸的蛋白质。CTGF可触发许多潜在纤维化的细胞过程，如细胞增殖、粘附、迁移、细胞外基质合成等，但其在急慢性心脏损伤中的作用尚不完全清楚。在这里，我们发现tgf - β是心肌成纤维细胞和心肌细胞中CTGF表达的特异性诱导剂。基于CTGF启动子的报告结构的活性与内源性CTGF表达相关，表明tgf - β极有可能通过激活其启动子诱导CTGF表达。CTGF的上调与纤维连接蛋白、I型胶原和纤溶酶原激活物抑制剂-1的产生增加相一致。环AMP刺激剂Forskolin阻断tgf - β诱导的CTGF表达，降低CTGF基础水平。而阻断MAP激酶信号通路的抑制剂（PD 98059）可显著增强tgf - β诱导的CTGF表达。此外，我们发现心肌梗死后2-16周大鼠心脏左心室和间隔中tgf - β和CTGF mrna均显著升高。这与这些动物心脏中纤维连接蛋白、I型和III型胶原mRNA水平的增加密切相关。在诊断为心脏缺血的患者的心脏样本中也检测到CTGF的显著上调。基于这些发现，我们提出CTGF是心脏中tgf - β信号传导的重要介质，该基因的异常表达可作为心脏纤维化的诊断标志物。(C) 2000年学术出版社。
Connective tissue growth factor (CTGF) is a cysteine-rich protein induced by transforming growth factor beta (TGF-beta) in connective tissue cells. CTGF can trigger many of the cellular processes underlying fibrosis, such as cell proliferation, adhesion, migration and the synthesis of extracellular matrix: however, its role in acute and chronic cardiac injury is not fully understood. Here, we show that TGF-beta is a specific inducer of CTGF expression in both cardiac fibroblasts and cardiac myocytes. The activity of a CTGF promoter-based reporter construct correlated with endogenous CTGF expression, suggesting that TGF-beta induces CTGF expression most likely by activating its promoter. Upregulation of CTGF coincided with an increase in fibronectin, collagen type I and plasminogen activator inhibitor-1 production. Forskolin, a stimulator of cyclic AMP, blocked TGF-beta induced CTGF expression and reduced the basal level of CTGF. whereas an inhibitor that blocks the MAP kinase signaling pathway (PD 98059) significantly enhanced TGF-beta induced CTGF expression. Furthermore, we found that both TGF-beta and CTGF mRNAs were significantly elevated in the left ventricles and septa of rat hearts 2-16 weeks following myocardial infarction. This correlated well with concomitant increases in fibronectin, and type I and type III collagen mRNA levels in these animal hearts. Significant upregulation of CTGF was also detected in human heart samples derived from patients diagnosed with cardiac ischemia. Based on these findings, we propose that CTGF is an important mediator of TGF-beta signaling in the heart and abnormal expression of this gene could be used as a diagnostic marker for cardiac fibrosis. (C) 2000 Academic Press.