Antioxidants relieve phosphatase inhibition and reduce PDGF signaling in cultured VSMCs and in restenosis
Antioxidants relieve phosphatase inhibition and reduce PDGF signaling in cultured VSMCs and in restenosis
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DOI：
10.1161/01.atv.0000246777.30819.85
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发表时间：
2006-12-01
影响因子：
8.7
通讯作者：
Ostman, Arne
中科院分区：
文献类型：
--
作者：
Kappert, Kai;Sparwel, Jan;Ostman, Arne
目的 - 生长因子和活性氧 (ROS) 诱导的 VSMC 激活与血管疾病有关。本研究调查了蛋白酪氨酸磷酸酶 (PTP) 的抑制性氧化是否有助于体外和体内 VSMC 中的信号传导，并分析了 ROS 和生长因子依赖性血管平滑肌细胞 (VSMC) 信号传导是否会被能够激活氧化 PTP 的抗氧化剂减弱。方法和结果 - 在有或没有抗氧化剂的情况下，分析了 H2O2 和血小板衍生生长因子 (PDGF) 在 VSMC 中诱导的信号传导N-乙酰半胱氨酸 (NAC) 和 tempol。确定了抗氧化剂对 PDGF 刺激的趋化性和增殖的影响。通过分析新内膜形成、细胞增殖、PDGF β 受体状态以及 PTP 表达和活性，在大鼠颈动脉球囊损伤模型中分析抗氧化剂的体内作用。 NAC 治疗可防止 H2O2 诱导的 PTP 抑制，并减少 H2O2 和配体诱导的 PDGF β 受体磷酸化、PDGF 诱导的增殖和 VSMC 的趋化性。抗氧化剂抑制新内膜形成，减少新内膜中的 PDGF 受体磷酸化，并增加 PTP 活性。结论 - PTP 抑制被确定为培养的 VSMC 中 H2O2 和 PDGF 诱导信号传导的内在成分。抗氧化剂导致体内PDGF β-受体磷酸化的减少以及PTP活性的增加表明氧化PTP的激活是抗氧化剂抗再狭窄作用的一种先前未被认识的机制。因此，总的来说，这些发现表明，氧化 PTP 的重新激活是一种新型的抗再狭窄策略。
Objective - Growth factor- and reactive oxygen species (ROS)-induced activation of VSMCs is involved in vascular disease. This study investigates whether inhibitory oxidation of protein tyrosine phosphatases (PTPs) contributes to signaling in VSMCs in vitro and in vivo, and analyzes whether ROS- and growth factor-dependent vascular smooth muscle cell (VSMC) signaling is blunted by antioxidants that are able to activate oxidized PTPs.Methods and Results - Signaling induced by H2O2 and platelet-derived growth factor (PDGF) was analyzed in VSMCs with or without the antioxidants N-acetyl-cysteine (NAC) and tempol. Effects of antioxidants on PDGF-stimulated chemotaxis and proliferation were determined. In vivo effects of antioxidants were analyzed in the rat carotid balloon-injury model, by analyzing neointima formation, cell proliferation, PDGF beta-receptor status, and PTP expression and activity. NAC treatment prevented H2O2-induced PTP inhibition, and reduced H2O2-and ligand-induced PDGF beta-receptor phosphorylation, PDGF-induced proliferation, and chemotaxis of VSMCs. Antioxidants inhibited neointima formation and reduced PDGF receptor phosphorylation in the neointima and also increased PTP activity.Conclusion - PTP-inhibition was identified as an intrinsic component of H2O2-and PDGF-induced signaling in cultured VSMCs. The reduction in PDGF beta-receptor phosphorylation in vivo, and the increase in PTP activity, by antioxidants indicate activation of oxidized PTPs as a previously unrecognized mechanism for the antirestenotic effects of antioxidants. The findings thus suggest, in general terms, reactivation of oxidized PTPs as a novel antirestenotic strategy.