Angiotensin II stimulates collagen synthesis in human vascular smooth muscle cells -: Involvement of the AT1 receptor, transforming growth factor-β, and tyrosine phosphorylation
Angiotensin II stimulates collagen synthesis in human vascular smooth muscle cells -: Involvement of the AT1 receptor, transforming growth factor-β, and tyrosine phosphorylation
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DOI：
10.1161/01.atv.19.8.1843
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发表时间：
1999-08-01
影响因子：
8.7
通讯作者：
Pickering, JG
中科院分区：
文献类型：
--
作者：
Ford, CM;Li, SH;Pickering, JG
血管紧张素II是血管张力和平滑肌细胞（SMC）生长的既定调节剂。然而，关于其对SMC胶原合成的影响的数据很少，并且没有关于这种作用的机制的数据。我们研究了血管紧张素II对人动脉平滑肌细胞胶原蛋白生成的影响，使用[H-3]脯氨酸摄取到胶原酶可消化的蛋白质中，并通过核糖核酸酶保护测定编码I型胶原蛋白（动脉中的主要胶原蛋白）的前α链的mRNA。这表明相对胶原蛋白合成速率呈剂量依赖性增加，前α 1（I）胶原蛋白mRNA丰度呈剂量依赖性增加，半数最大效应为1.7 nmol/L。血管紧张素II刺激的胶原蛋白表达与转化生长因子-β（TGF-β）产生的6倍增加有关，并被TGF-β的中和抗体抑制。胶原蛋白的生成和TGF-β的释放都被AT（2）特异性拮抗剂氯沙坦抑制，但不被AT（2）受体拮抗剂PD 123319抑制。为了确定酪氨酸磷酸化是否在功能上与胶原合成相关，我们研究了酪氨酸激酶的两种不同机制抑制剂染料木黄酮和酪氨酸磷酸化抑制剂A25的作用。这些抑制剂废除血管紧张素II介导的前胶原mRNA的表达和血管紧张素II介导的TGF-β的生产，而无活性的同源物tyrphostin Al没有效果。我们的结论是，血管紧张素II刺激胶原蛋白的生产在人类动脉平滑肌细胞通过AT，受体和自分泌循环的TGF-β，诱导需要苯乙烯磷酸化。
Angiotensin II is an established regulator of vascular tone and smooth muscle cell (SMC) growth. However, there are little data about its effect on collagen synthesis by SMCs and none regarding the mechanism of such an effect. We studied the effect of angiotensin II on collagen production by human arterial SMCs, using uptake of [H-3]proline into collagenase-digestible proteins, and by ribonuclease protection assay for mRNA encoding the proal chain of type I collagen, the major collagen in arteries. This revealed a dose-dependent increase in relative collagen synthesis rate and a dose-dependent increase in pro alpha 1(I) collagen mRNA abundance, with the half-maximal effect at 1.7 nmol/L. Angiotensin II-stimulated collagen expression was associated with a 6-fold increase in transforming growth factor-beta (TGF-beta) production and was inhibited by a neutralizing antibody to: TGF-beta. Both collagen production and TGF-beta release were inhibited by the AT(2)-specific antagonist, losartan, but not by the AT(2) receptor antagonist, PD123319. To determined if tyrosine phosphorylation was functionally linked to collagen synthesis, we studied the effect of 2 mechanistically distinct inhibitors of tyrosine kinase, genistein, and tyrphostin A25. These inhibitors abrogated angiotensin II-mediated procollagen mRNA expression and angiotensin II-mediated TGF-beta production, whereas the inactive homolog tyrphostin Al had no effect. We conclude that angiotensin II stimulates collagen production in human arterial SMCs via the AT, receptor and an autocrine loop of TGF-beta, induction of which require styrosine phosphorylation.