Rodriguez-Vita Juan, Ruiz-Ortega Marta, Rupérez Mónica, Esteban Vanessa, Sanchez-López Elsa, Plaza Juan José, Egido Jesús
Vascular and Renal Research Laboratory, Fundación Jiménez Díaz, Universidad Autónoma Madrid, Avda. Reyes Católicos, 2, 28040 Madrid, Spain.
Circ Res. 2005 Jul 22;97(2):125-34. doi: 10.1161/01.RES.0000174614.74469.83. Epub 2005 Jun 23.
Endothelin (ET)-1 is a potent vasoconstrictor that participates in cardiovascular diseases. Connective tissue growth factor (CTGF) is a novel fibrotic mediator that is overexpressed in human atherosclerotic lesions, myocardial infarction, and experimental models of hypertension. In vascular smooth muscle cells (VSMCs), CTGF regulates cell proliferation/apoptosis, migration, and extracellular matrix (ECM) accumulation. Our aim was to investigate whether ET-1 could regulate CTGF and to investigate the potential role of ET-1 in vascular fibrosis. In growth-arrested rat VSMCs, ET-1 upregulated CTGF mRNA expression, promoter activity, and protein production. The blockade of CTGF by a CTGF antisense oligonucleotide decreased FN and type I collagen expression in ET-1-treated cells, showing that CTGF participates in ET-1-induced ECM accumulation. The ETA, but not ETB, antagonist diminished ET-1-induced CTGF expression gene and production. Several intracellular signals elicited by ET-1, via ETA receptors, are involved in CTGF synthesis, including activation of RhoA/Rho-kinase and mitogen-activated protein kinase and production of reactive oxygen species. CTGF is a mediator of TGF-beta- and angiotensin (Ang) II-induced fibrosis. In VSMCs, ET-1 did not upregulate TGF-beta gene or protein. The presence of neutralizing transforming growth factor (TGF)-beta antibody did not modify ET-1-induced CTGF production, showing a TGF-beta-independent regulation. We have also found an interrelationship between Ang II and ET-1 because the ETA antagonist diminished CTGF upregulation caused by Ang II. Collectively, our results show that, in cultured VSMCs, ET-1, independently of TGF-beta and through the activation of several intracellular signals via ETA receptors, regulates CTGF. This novel finding suggests that CTGF could be a mediator of the profibrotic effects of ET-1 in vascular diseases.
内皮素（ET）-1是一种强效血管收缩剂，参与心血管疾病的发生。结缔组织生长因子（CTGF）是一种新型纤维化介质，在人类动脉粥样硬化病变、心肌梗死及高血压实验模型中过度表达。在血管平滑肌细胞（VSMC）中，CTGF调节细胞增殖/凋亡、迁移及细胞外基质（ECM）积聚。我们的目的是研究ET-1是否能调节CTGF，并探讨ET-1在血管纤维化中的潜在作用。在生长停滞的大鼠VSMC中，ET-1上调CTGF mRNA表达、启动子活性及蛋白生成。CTGF反义寡核苷酸对CTGF的阻断降低了ET-1处理细胞中纤连蛋白和I型胶原的表达，表明CTGF参与ET-1诱导的ECM积聚。ETA拮抗剂而非ETB拮抗剂可减少ET-1诱导的CTGF表达及生成。ET-1通过ETA受体引发的几种细胞内信号参与CTGF合成，包括RhoA/Rho激酶的激活、丝裂原活化蛋白激酶的激活及活性氧的生成。CTGF是转化生长因子（TGF）-β和血管紧张素（Ang）II诱导纤维化的介质。在VSMC中，ET-1未上调TGF-β基因或蛋白。中和性转化生长因子（TGF）-β抗体的存在并未改变ET-1诱导的CTGF生成，表明其调节不依赖于TGF-β。我们还发现Ang II与ET-1之间存在相互关系，因为ETA拮抗剂可减少Ang II引起的CTGF上调。总体而言，我们的结果表明，在培养的VSMC中，ET-1不依赖于TGF-β并通过ETA受体激活多种细胞内信号来调节CTGF。这一新发现提示CTGF可能是ET-1在血管疾病中促纤维化作用的介质。
