Induction of connective tissue growth factor by angiotensin II - Integration of signaling pathways
Induction of connective tissue growth factor by angiotensin II - Integration of signaling pathways
复制标题
DOI：
10.1161/01.atv.0000092913.60428.e6
复制
发表时间：
2003-10-01
影响因子：
8.7
通讯作者：
Goppelt-Struebe, M
中科院分区：
文献类型：
--
作者：
Iwanciw, D;Rehm, M;Goppelt-Struebe, M
目的-血管紧张素II被认为是心血管病理学的主要介质之一。由于结缔组织生长因子（CTGF）参与的病理生理过程中的纤维化疾病的基础，其调节血管紧张素II investigated.Methods和结果-在2肾，1夹模型肾血管性高血压，CTGF的表达增加是可检测的肥厚左心室。通过激活血管紧张素II 1型受体，血管紧张素II引起CTGF mRNA和蛋白在人成纤维细胞系中的快速表达。p42/44丝裂原活化蛋白（MAP）激酶信号通路的激活被证明是血管紧张素II刺激的CTGF表达所必需的。毛喉素抑制MAP激酶激活阻止CTGF诱导。通过辛伐他汀或毒素B预处理细胞抑制小GTP酶的异戊二烯化，将基础CTGF表达降低至检测限以下，并防止血管紧张素II诱导。Y27632对RhoA信号传导的特异性干扰主要降低了基础CTGF表达。辛伐他汀对血管紧张素II 1型受体的表达无显著降低。这些数据表明Rho信号和血管紧张素II激活的MAP激酶pathways.Conclusions -血管紧张素II直接诱导CTGF是指示CTGF在血管紧张素II介导的纤维化中的作用，并且可能是抗纤维化干预的目标。
Objective - Angiotensin II is recognized as one of the major mediators of cardiovascular pathology. Because connective tissue growth factor (CTGF) is involved in the pathophysiologic processes underlying fibrotic diseases, its regulation by angiotensin II was investigated.Methods and Results - In the 2-kidney, 1-clip model of renovascular hypertension, increased expression of CTGF was detectable in the hypertrophic left ventricle. By activation of angiotensin II type 1 receptors, angiotensin II caused rapid expression of CTGF mRNA and protein in a human fibroblast cell line. Activation of the p42/44 mitogen-activated protein (MAP) kinase signaling pathway proved to be essential for angiotensin II - stimulated CTGF expression. Inhibition of MAP kinase activation by forskolin prevented CTGF induction. Inhibition of the isoprenylation of small GTPases by simvastatin or pretreatment of the cells with toxin B reduced basal CTGF expression below detection limits and prevented induction by angiotensin II. Specific interference with RhoA signaling by Y27632 primarily reduced basal CTGF expression. There was no significant reduction of expression of angiotensin II type 1 receptors by simvastatin. These data indicate cooperation between the Rho signaling and the angiotensin II-activated MAP kinase pathways.Conclusions - Direct induction of CTGF by angiotensin II is indicative of a role for CTGF in angiotensin II - mediated fibrosis and might be a target of antifibrotic interventions.