Mechanisms related to NO-induced motility in differentiated rat aortic smooth muscle cells.
Mechanisms related to NO-induced motility in differentiated rat aortic smooth muscle cells.
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与 NO 诱导分化的大鼠主动脉平滑肌细胞运动相关的机制。
DOI：
10.1152/ajpheart.00342.2010
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发表时间：
2011
期刊：
影响因子：
--
通讯作者：
Hassid,Aviv
中科院分区：
文献类型：
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作者：
Pu,Qinghua;Zhuang,Daming;Thakran,Shalini;Hassid,Aviv
一氧化氮（NO）被认为是血管细胞增殖、运动和新生内膜形成的重要抑制剂。这种作用部分是通过蛋白酪氨酸磷酸酶（PTP）1B的上调介导的。相反，研究报告称，在高胰岛素血症小鼠中，喂食高脂肪饮食，一氧化氮增强血管重塑，而一氧化氮缺失则减弱血管重塑。我们已经报道，在胰岛素处理的分化培养平滑肌细胞中，NO诱导了一种依赖于Src同源-2结构域PTP 2 （SHP2）上调的致运动作用。在本研究中，我们描述了与一氧化氮致运动作用相关的新机制。用选择性血管紧张素1型受体拮抗剂氯沙坦而不使用选择性血管紧张素2型受体拮抗剂PD-123319处理培养细胞，可阻断NO和胰岛素的共生能力。胰岛素和NO分别使培养液中ANG II的分泌量增加了2倍和2.5倍（P< 0.05），而用ANG II处理细胞可以发现NO的致运动作用（比对照组高1.4倍，P< 0.05），使PTP1B水平降低到对照组的45% （P< 0.05）。抑制PTP1B功能足以揭示NO的致运动作用。胰岛素抑制PTP1B活性的能力被氯沙坦阻断，暗示ANG II的功能介导了这一作用。胰岛素和ANG II均可诱导磷脂酰肌醇3-激酶(PI3K)-δ上调2 - 3倍（P< 0.05），这是揭示no诱导的运动发生所必需和充分的作用。最后，抑制PTP1B功能增强，而过表达PTP1B抑制shp2诱导的运动发生。这些结果支持了胰岛素和NO共生效应通过ANG ii介导的作用发生的假设，包括抑制PTP1B和上调PI3K-δ和SHP2。
Nitric oxide (NO) is thought to play an important role as an inhibitor of vascular cell proliferation, motility, and neointima formation. This effect is mediated, in part, via the upregulation of protein tyrosine phosphatase (PTP)1B. Conversely, studies have reported that in presumably hyperinsulinemic mice fed a high-fat diet, NO enhances vascular remodeling, whereas a deficit of NO attenuates vascular remodeling. We have reported that in differentiated cultured smooth muscle cells treated with insulin, NO induces a motogenic effect that is dependent on Src homology-2 domain PTP 2 (SHP2) upregulation. In the present study, we describe novel mechanisms relevant to the motogenic effect of NO. Treatment of cultured cells with the selective angiontensin type 1 receptor antagonist losartan, but not with the selective angiotensin type 2 receptor antagonist PD-123319, blocked the comotogenic capacity of NO and insulin. Insulin and NO increased the secretion of ANG II into the culture media by 2- and 2.5-fold (P< 0.05), respectively, whereas treatment of cells with ANG II uncovered the motogenic effect of NO (1.4-fold above control,P< 0.05) and decreased the levels of PTP1B to 45% of control (P< 0.05). Suppression of PTP1B function was sufficient to uncover the motogenic effect of NO. The capacity of insulin to suppress PTP1B activity was blocked by losartan, implicating ANG II function in mediating this effect. Both insulin and ANG II induced the upregulation of phosphatidyl inositol 3-kinase (PI3K)-δ by two- to threefold (P< 0.05), and this effect was both necessary and sufficient to uncover NO-induced motogenesis. Finally, suppression of PTP1B function potentiated, whereas overexpression of PTP1B inhibited, SHP2-induced motogenesis. These results support the hypothesis that the comotogenic effect of insulin and NO occurs via an ANG II-mediated effect involving the suppression of PTP1B and upregulation of PI3K-δ and SHP2.