Connective tissue growth factor is a mediator of angiotensin II-induced fibrosis
Connective tissue growth factor is a mediator of angiotensin II-induced fibrosis
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DOI：
10.1161/01.cir.0000089129.51288.ba
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发表时间：
2003-09-23
期刊：
影响因子：
37.8
通讯作者：
Ruiz-Ortega, M
中科院分区：
文献类型：
--
作者：
Rupérez, M;Lorenzo, O;Ruiz-Ortega, M
血管紧张素II（Ang II）参与血管损伤过程中纤维化的发展。结缔组织生长因子（CTGF）是一种新的纤维化介质。然而，CTGF和血管紧张素II之间的潜在联系还没有被investigated.Methods和Results-In体内血管紧张素II的影响进行了研究，通过全身灌注到正常大鼠，以评估CTGF和细胞外基质蛋白（ECM）的表达免疫组化。在血管紧张素II灌注大鼠的主动脉中，CTGF染色显著增加，观察到ECM过度表达。AT（1）拮抗剂减少CTGF和ECM。在生长停滞的血管平滑肌细胞中，Ang II在1小时后诱导CTGF mRNA表达，并在24小时内保持升高，并增加CTGF蛋白的产生，并在72小时内增加。AT（1）拮抗剂阻断Ang II诱导的CTGF基因和蛋白表达。早期CTGF上调不依赖于新蛋白质的合成。由Ang II引起的几种细胞内信号参与CTGF合成，包括蛋白激酶C活化、活性氧和转化生长因子β内源性产生。与CTGF反义寡核苷酸一起孵育降低了由Ang II引起的CTGF和纤连蛋白上调。结论我们的结果表明，Ang II通过AT（1）在体内和体外增加血管细胞中的CTGF。这一新的发现表明，CTGF可能是血管紧张素II在血管疾病中的促纤维化作用的介质。
Background-Angiotensin II (Ang II) participates in the development of fibrosis during vascular damage. Connective tissue growth factor (CTGF) is a novel fibrotic mediator. However, the potential link between CTGF and Ang II has not been investigated.Methods and Results-In vivo Ang II effects were studied by systemic infusion into normal rats to evaluate CTGF and extracellular matrix protein (ECM) expression by immunohistochemistry. In aorta of Ang II-infused rats, CTGF staining was markedly increased and ECM overexpression was observed. An AT(1) antagonist diminished CTGF and ECM. In growth-arrested vascular smooth muscle cells, Ang II induced CTGF mRNA expression after 1 hour, remained elevated up to 24 hours, and increased CTGF protein production, which was increased up to 72 hours. The AT(1) antagonist blocked Ang II-induced CTGF gene and protein expression. Early CTGF upregulation is independent of new protein synthesis. Several intracellular signals elicited by Ang II are involved in CTGF synthesis, including protein kinase C activation, reactive oxygen species, and transforming growth factor-beta endogenous production. Incubation with a CTGF antisense oligonucleotide decreased CTGF and fibronectin upregulation caused by Ang II.Conclusions-Our results show that Ang II, via AT(1), increases CTGF in vascular cells both in vivo and in vitro. This novel finding suggests that CTGF may be a mediator of the profibrogenic effects of Ang II in vascular diseases.