Angiotensin II-stimulated collagen synthesis in aortic adventitial fibroblasts is mediated by connective tissue growth factor
Angiotensin II-stimulated collagen synthesis in aortic adventitial fibroblasts is mediated by connective tissue growth factor
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DOI：
10.1291/hypres.31.1233
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发表时间：
2008-06-01
影响因子：
5.4
通讯作者：
Zhu, Ding-liang
中科院分区：
文献类型：
--
作者：
Che, Zai-qian;Gao, Ping-jin;Zhu, Ding-liang
血管紧张素II （angii）是一种有效的血管重构介质，可以刺激血管细胞内细胞外基质的合成。近年来研究表明结缔组织生长因子（CTGF）参与胶原蛋白的合成。越来越多的证据表明，外基质成纤维细胞（AFs）积极参与血管重构。然而，AFs的胶原合成是否由CTGF介导，或者是否与Ang II相关，目前还没有研究。本研究旨在确定CTGF是否在AFs中表达，如果表达，AFs产生的CTGF是否参与胶原合成。从Wistar-Kyoto大鼠（WKY）胸主动脉中分离AFs。采用Western blot或real-time PCR检测CTGF的表达。用[3h]脯氨酸掺入法测定胶原合成。我们的结果表明CTGF在AFs中表达并分泌到培养基中。Ang II增加CTGF mRNA和蛋白表达呈时间和剂量依赖性，当Ang II剂量为10(-7)mol/L时，蛋白表达在24 h达到最大，这种增加被Ang II受体1型（at (1)- r）拮抗剂氯沙坦抑制，但不被Ang II受体2型（at (2)- r）拮抗剂PD123319抑制。Ang II以剂量依赖性刺激[H-3]脯氨酸并入培养的AFs，这种作用被CTGF反义寡核苷酸抑制。pcDNA3.1(+)/CTGF过表达CTGF可增加培养AFs中[3 H]脯氨酸的掺入。结果表明，在培养的AFs中，Ang II通过AT(1)-R增加CTGF的产生，AT(1)-R可能是Ang II合成胶原的介质。这一发现提示CTGF可能是血管疾病抗纤维化治疗的新靶点。
Angiotensin II (Ang II), a potent mediator of vascular remodeling, can stimulate the synthesis of extracellular matrix in vascular cells. Recent studies indicate that connective tissue growth factor (CTGF) is involved in collagen synthesis. There is also increasing evidence that adventitial fibroblasts (AFs) are actively involved in vascular remodeling. However, whether collagen synthesis by AFs is mediated by CTGF, or whether it is relevant to Ang II, has not been studied. The present study was conducted to determine whether CTGF is expressed in AFs, and if so, whether the CTGF produced by AFs participates in collagen synthesis. The AFs were isolated from thoracic aorta of Wistar-Kyoto rats (WKY). The expression of CTGF was measured by Western blot or real-time PCR. Collagen synthesis was assessed by [3 H]proline incorporation. Our results suggested that CTGF was expressed in AFs and secreted into medium. Ang II increased CTGF mRNA and protein expression in a time- and dose-dependent manner, with the maximal protein increase occurring at 24 h with an Ang II dose of 10(-7) mol/L, and this increase was inhibited by the Ang II receptor type 1 (AT(1)-R) antagonist losartan, but not by the Ang II receptor type 2 (AT(2)-R) antagonist PD123319. Ang II dose-dependently stimulated the incorporation of [H-3]proline into cultured AFs, and this effect was inhibited by a CTGF antisense oligodeoxynucleotide. Overexpression of CTGF by pcDNA3.1(+)/CTGF increased [3 H]proline incorporation in cultured AFs. The results demonstrated that, In cultured AFs, Ang II increased CTGF production via AT(1)-R, which could be mediators of collagen synthesis by Ang II. This finding suggests that CTGF might be a novel target for antifibrotic therapy in vascular diseases.