title: Anti-β2GPI antibodies stimulate endothelial cell microparticle release via a nonmuscle myosin II motor protein-dependent pathway.
abstract: The antiphospholipid syndrome is characterized by thrombosis and recurrent fetal loss in patients with antiphospholipid antibodies (APLAs). Most pathogenic APLAs are directed against β2-glycoprotein I (β2GPI), a plasma phospholipid binding protein. One mechanism by which circulating antiphospholipid/anti-β2GPI antibodies may promote thrombosis is by inducing the release of procoagulant microparticles from endothelial cells. However, there is no information available concerning the mechanisms by which anti-β2GPI antibodies induce microparticle release. In seeking to identify proteins phosphorylated during anti-β2GPI antibody-induced endothelial activation, we observed phosphorylation of nonmuscle myosin II regulatory light chain (RLC), which regulates cytoskeletal assembly. In parallel, we observed a dramatic increase in the formation of filamentous actin, a two- to fivefold increase in the release of endothelial cell microparticles, and a 10- to 15-fold increase in the expression of E-selectin, intercellular adhesion molecule 1, vascular cell adhesion molecule 1, and tissue factor messenger RNA. Microparticle release, but not endothelial cell surface E-selectin expression, was blocked by inhibiting RLC phosphorylation or nonmuscle myosin II motor activity. These results suggest that distinct pathways, some of which mediate cytoskeletal assembly, regulate the endothelial cell response to anti-β2GPI antibodies. Inhibition of nonmuscle myosin II activation may provide a novel approach for inhibiting microparticle release by endothelial cells in response to anti-β2GPI antibodies.
authors: Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, OH;
authors: Venkaiah
authors: V
authors: Betapudi
authors: George
authors: G
authors: Lominadze
authors: Linda
authors: L
authors: Hsi
authors: Belinda
authors: B
authors: Willard
authors: Meifang
authors: M
authors: Wu
authors: Keith R
authors: KR
authors: McCrae
mesh_terms: D000818:Animals; D017152:Antibodies, Antiphospholipid / Q000097:blood / Q000276:immunology*; D016736:Antiphospholipid Syndrome / Q000097:blood / Q000150:complications / Q000276:immunology*; D055252:Cell-Derived Microparticles / Q000276:immunology / Q000378:metabolism; D019040:E-Selectin / Q000378:metabolism; D042783:Endothelial Cells / Q000276:immunology* / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008954:Models, Biological; D020409:Molecular Motor Proteins / Q000276:immunology / Q000378:metabolism; D018994:Myosin Light Chains / Q000276:immunology / Q000378:metabolism; D009219:Myosin-Light-Chain Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism; D024507:Nonmuscle Myosin Type IIA / Q000276:immunology* / Q000378:metabolism; D010766:Phosphorylation; D011817:Rabbits; D015398:Signal Transduction; D013927:Thrombosis / Q000097:blood / Q000209:etiology / Q000276:immunology; D053482:beta 2-Glycoprotein I / Q000276:immunology*; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D017152:Antibodies, Antiphospholipid; D019040:E-Selectin; D020409:Molecular Motor Proteins; D018994:Myosin Light Chains; C546936:SELE protein, human; D053482:beta 2-Glycoprotein I; C515851:ROCK1 protein, human; C515852:ROCK2 protein, human; D054460:rho-Associated Kinases; D009219:Myosin-Light-Chain Kinase; D024507:Nonmuscle Myosin Type IIA
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