Endothelin (ET)-1 is a vasoconstrictor involved in cardiovascular diseases. Connective tissue growth factor/CCN2 (CTGF) is a fibrotic mediator overexpressed in human atherosclerotic lesions, myocardial infarction, and hypertension. In different cell types CTGF regulates cell proliferation/apoptosis, migration, and extracellular matrix (ECM) accumulation and plays important roles in angiogenesis, chondrogenesis, osteogenesis, tissue repair, cancer and fibrosis. In the present study, we investigated the ET-1 signaling which triggers CTGF expression in cultured adult mouse atrial-muscle HL-1 cells used as a model system. ET-1 activated the CTGF promoter and induced CTGF expression at both mRNA and protein levels. Real-time PCR analysis revealed CTGF induction also in isolated rat heart preparations perfused with ET-1. Several intracellular signals elicited by ET-1 via ET receptors and even Epidermal Growth Factor Receptor (EGFR) contributed to the up-regulation of CTGF, including ERK activation and induction of the AP-1 components c-fos and c-jun, as also evaluated by ChIP analysis. Moreover, in cells treated with ET-1 the expression of ECM component decorin was abolished by CTGF silencing, indicating that CTGF is involved in ET-1 induced ECM accumulation not only in a direct manner but also through downstream effectors. Collectively, our data indicate that CTGF could be a mediator of the profibrotic effects of ET-1 in cardiomyocytes. CTGF inhibitors should be considered in setting a comprehensive pharmacological approach towards ET-1 induced cardiovascular diseases.

中文翻译：

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内皮素-1诱导心肌细胞中结缔组织生长因子的表达。

内皮素（ET）-1是涉及心血管疾病的血管收缩药。结缔组织生长因子/ CCN2（CTGF）是在人类动脉粥样硬化病变，心肌梗塞和高血压中过表达的纤维化介质。在不同的细胞类型中，CTGF调节细胞增殖/凋亡，迁移和细胞外基质（ECM）积累，并在血管生成，软骨生成，成骨，组织修复，癌症和纤维化中发挥重要作用。在本研究中，我们调查了ET-1信号，该信号触发了培养的成年小鼠心房肌HL-1细胞（用作模型系统）中CTGF的表达。ET-1激活CTGF启动子，并在mRNA和蛋白水平上诱导CTGF表达。实时PCR分析显示，在灌注了ET-1的离体大鼠心脏制剂中，CTGF也被诱导。ET-1经由ET受体甚至表皮生长因子受体（EGFR）引发的几种细胞内信号促成CTGF的上调，包括ERK激活和AP-1组分c-fos和c-jun的诱导，以及通过ChIP分析进行评估。此外，在用ET-1处理的细胞中，CTGF沉默消除了ECM成分除蛋白的表达，这表明CTGF不仅以直接方式而且通过下游效应子参与ET-1诱导的ECM积累。总的来说，我们的数据表明CTGF可能是ET-1在心肌细胞中的纤维化作用的介质。在制定针对ET-1诱发的心血管疾病的综合药理方法时，应考虑使用CTGF抑制剂。