Journal
BLOOD
Volume 122, Issue 23, Pages 3808-3817Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2013-03-490318
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Funding
- National Institutes of Health, National Heart, Lung, and Blood Institute [R01HL089796, P50HL081011]
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The antiphospholipid syndrome is characterized by thrombosis and recurrent fetal loss in patients with antiphospholipid antibodies (APLAs). Most pathogenic APLAs are directed against beta(2)-glycoprotein I (beta(2)GPI), a plasma phospholipid binding protein. One mechanism by which circulating antiphospholipid/anti-beta(2)GPI 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-beta(2)GPI antibodies induce microparticle release. In seeking to identify proteins phosphorylated during anti-beta(2)GPI 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-beta(2)GPI antibodies. Inhibition of nonmuscle myosin II activation may provide a novel approach for inhibiting microparticle release by endothelial cells in response to anti-beta(2)GPI antibodies.
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