NITRIC-OXIDE INHIBITS ANGIOTENSIN-II-INDUCED MIGRATION OF RAT AORTIC SMOOTH-MUSCLE CELL - ROLE OF CYCLIC-NUCLEOTIDES AND ANGIOTENSIN(1) RECEPTORS
NITRIC-OXIDE INHIBITS ANGIOTENSIN-II-INDUCED MIGRATION OF RAT AORTIC SMOOTH-MUSCLE CELL - ROLE OF CYCLIC-NUCLEOTIDES AND ANGIOTENSIN(1) RECEPTORS
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DOI：
10.1172/jci118014
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发表时间：
1995-07-01
影响因子：
15.9
通讯作者：
LUSCHER, TF
中科院分区：
文献类型：
--
作者：
DUBEY, RK;JACKSON, EK;LUSCHER, TF
一氧化氮（NO）和血管紧张素II（AII）可影响血管平滑肌细胞（SMC）的增殖。然而，这些物质对SMC迁移的影响，这一在血管病理生理学方面同样重要的现象，却很少受到关注。本研究的目的是：（a）确定NO是否抑制AII诱导的血管SMC迁移；（b）研究NO和AII在SMC迁移上相互作用的机制；（c）评估介导AII诱导的SMC迁移的AII受体亚型。使用改良的博伊登室（带有明胶包被的聚碳酸酯膜的Transwell小室，孔径8μm）评估大鼠SMC的迁移。AII以浓度依赖的方式刺激SMC迁移，这种作用被硝普钠（SNP）和S - 亚硝基 - N - 乙酰青霉胺（SNAP）所抑制。在L - 精氨酸而非D - 精氨酸存在的情况下，诱导型NO合酶的诱导剂白细胞介素 - 1β（IL - 1β）也抑制AII诱导的SMC迁移，并且这种作用被NO合酶抑制剂N - 硝基 - L - 精氨酸甲酯所阻断。NO供体对AII诱导的SMC迁移的作用被8 - 溴 - 环鸟苷酸（8 - bromo - cGMP）所模拟。此外，SNAP的抗迁移作用被LY83583（一种可溶性鸟苷酸环化酶抑制剂）和KT5823（一种环鸟苷酸依赖性蛋白激酶抑制剂）部分抑制。尽管8 - 溴 - 环腺苷酸（8 - bromo - cAMP）也模拟NO供体的抗迁移作用，但SNAP的抗迁移作用不受2',5' - 二脱氧腺苷（一种腺苷酸环化酶抑制剂）或（R） - 对 - 腺苷 - 3',5' - 环硫代磷酸酯（一种环腺苷酸依赖性蛋白激酶抑制剂）的影响。低浓度的亚型AT₁受体拮抗剂CGP 48933，而非亚型AT₂受体拮抗剂CGP 42112，阻断AII诱导的SMC迁移。这些发现表明：（a）NO抑制AII诱导的血管SMC迁移；（b）NO的抗迁移作用部分通过环鸟苷酸依赖性机制介导；（c）AII通过AT₁受体刺激SMC迁移。
Nitric oxide (NO) and angiotensin II (AII) can effect vascular smooth muscle cell (SMC) proliferation. However, the effects of such agents on SMC migration, an equally important phenomenon with regard to vascular pathophysiology, have received little attention. The objectives of the present study were: (a) to determine whether NO inhibits AII-induced migration of vascular SMCs; (b) to investigate the mechanism of the interaction of NO and An on SMC migration; and (c) to evaluate the AII receptor subtype that mediates AII-induced SMC migration. Migration of rat SMCs was evaluated using a modified Boydens Chamber (transwell inserts with gelatin-coated polycarbonate membranes, 8 mu m pore size). AII stimulated SMC migration in a concentration-dependent manner, and this effect was inhibited by sodium nitroprusside (SNP) and S-nitroso-N-acetylpenicillamine (SNAP). In the presence of L-arginine, but not D-arginine, IL-1 beta, an inducer of inducible NO synthase, also inhibited AII-induced SMC migration, and this effect was prevented by the NO-synthase inhibitor, N-nitro-L-arginine methyl ester. The effects of NO donors on AII-induced SMC migration were mimicked by 8-bromo-cGMP. Also, the antimigratory effects of SNAP were partially inhibited by LY83583 (an inhibitor of Soluble guanylyl cyclase) and by KT5823 (an inhibitor of cGMP-dependent protein kinase). Although 8-bromo-cAMP (cAMP) also mimicked the antimigratory effects of NO donors, the antimigratory effects of SNAP were not altered by 2',5' -dideoxyadenosine (an inhibitor of adenyl cyclase) or by (R)-p-adenosine-3',5'-cyclic phosphorothioate (an inhibitor of the cAMP-dependent protein kinase). Low concentrations of the subtype AT(1)-receptor antagonist CGP 48933, but not the subtype AT(2)-receptor antagonist CGP 42112, blocked AII-induced SMC migration. These findings indicate that (a) NO inhibits AII-induced migration of vascular SMCs; (6) the antimigratory effect of NO is mediated in part via a cGMP-dependent mechanism; and (c) AII stimulates SMC migration via an AT(1) receptor.