Endothelial Microparticle Formation by Angiotensin II Is Mediated via Ang II Receptor Type I/NADPH Oxidase/Rho Kinase Pathways Targeted to Lipid Rafts
Endothelial Microparticle Formation by Angiotensin II Is Mediated via Ang II Receptor Type I/NADPH Oxidase/Rho Kinase Pathways Targeted to Lipid Rafts
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DOI：
10.1161/atvbaha.110.222703
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发表时间：
2011-08-01
影响因子：
8.7
通讯作者：
Touyz, Rhian M.
中科院分区：
文献类型：
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作者：
Burger, Dylan;Montezano, Augusto C.;Touyz, Rhian M.
目的-循环微粒在心血管疾病中增加，其本身可能促进氧化应激和炎症。它们形成和信号传导的分子机制尚不清楚。我们研究了活性氧 (ROS)、Rho 激酶和脂筏在微粒形成中的作用，并检查了它们在内皮细胞 (EC) 中的功能意义。方法和结果 - 通过膜联蛋白 V 或 CD144 染色和电子显微镜评估血管紧张素 II (Ang II) 刺激的 EC 和载脂蛋白 E-/- 小鼠的微粒形成。 Ang II 促进微粒形成并增加 EC O-2((.) over bar) 生成和 Rho 激酶活性。厄贝沙坦（Ang II 受体 I 型阻断剂）和法舒地尔（Rho 激酶抑制剂）可抑制 Ang II 刺激作用。甲基-β-环糊精和制霉菌素会破坏脂筏/小凹，阻止微粒释放。在微粒刺激的 EC 中评估的功能反应显示，O-2((.) over bar) 产生增加，血管细胞粘附分子/血小板-EC 粘附分子表达增强，巨噬细胞粘附增强。表皮生长因子受体的抑制作用阻断了微粒的促氧化和促炎作用。体外观察结果在载脂蛋白 E-/- 小鼠中得到证实，该小鼠表现出血管炎症和高水平的循环内皮微粒，夹竹桃麻素可降低这些效应。结论-我们证明了 Ang II 对内皮微粒释放的直接作用，这是通过 NADPH 氧化酶、ROS 和针对脂筏的 Rho 激酶介导的。微粒本身刺激内皮活性氧的形成和炎症反应。我们的研究结果表明，Ang II 通过其自身的内皮衍生微粒促进 EC 损伤的前馈系统。 （动脉硬化血栓 Vasc Biol.2011；31：1898-1907。）
Objective-Circulating microparticles are increased in cardiovascular disease and may themselves promote oxidative stress and inflammation. Molecular mechanisms underlying their formation and signaling are unclear. We investigated the role of reactive oxygen species (ROS), Rho kinase, and lipid rafts in microparticle formation and examined their functional significance in endothelial cells (ECs).Methods and Results-Microparticle formation from angiotensin II (Ang II)-stimulated ECs and apolipoprotein E-/- mice was assessed by annexin V or by CD144 staining and electron microscopy. Ang II promoted microparticle formation and increased EC O-2((.) over bar) generation and Rho kinase activity. Ang II-stimulated effects were inhibited by irbesartan (Ang II receptor type I blocker) and fasudil (Rho kinase inhibitor). Methyl-beta-cyclodextrin and nystatin, which disrupt lipid rafts/caveolae, blocked microparticle release. Functional responses, assessed in microparticle-stimulated ECs, revealed increased O-2((.) over bar) production, enhanced vascular cell adhesion molecule/platelet-EC adhesion molecule expression, and augmented macrophage adhesion. Inhibition of epidermal growth factor receptor blocked the prooxidative and proinflammatory effects of microparticles. In vitro observations were confirmed in apolipoprotein E-/- mice, which displayed vascular inflammation and high levels of circulating endothelial microparticles, effects that were reduced by apocynin.Conclusion-We demonstrated direct actions of Ang II on endothelial microparticle release, mediated through NADPH oxidase, ROS, and Rho kinase targeted to lipid rafts. Microparticles themselves stimulated endothelial ROS formation and inflammatory responses. Our findings suggest a feedforward system whereby Ang II promotes EC injury through its own endothelial-derived microparticles. (Arterioscler Thromb Vasc Biol. 2011; 31: 1898-1907.)