Endothelial Microparticle Formation by Angiotensin II Is Mediated via Ang II Receptor Type I/NADPH Oxidase/Rho Kinase Pathways Targeted to Lipid Rafts

被引:189
作者
Burger, Dylan [1 ]
Montezano, Augusto C. [1 ]
Nishigaki, Nobuhiro [1 ]
He, Ying [1 ]
Carter, Anthony [1 ]
Touyz, Rhian M. [1 ]
机构
[1] Univ Ottawa, OHRI, Kidney Res Ctr, Canada Res Chair Hypertens, Ottawa, ON K1H 8M5, Canada
关键词
angiotensin II; endothelium; reactive oxygen species; signal transduction; microparticles; MONOCYTE-DERIVED MICROPARTICLES; SMOOTH-MUSCLE-CELLS; NADPH OXIDASE; SUPEROXIDE-PRODUCTION; NAD(P)H OXIDASE; IN-VITRO; CIRCULATING MICROPARTICLES; HYPERTENSIVE PATIENTS; OXIDATIVE STRESS; GROWTH-FACTOR;
D O I
10.1161/ATVBAHA.110.222703
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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.)
引用
收藏
页码:1898 / 1907
页数:10
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