Antiphospholipid antibodies promote leukocyte-endothelial cell adhesion and thrombosis in mice by antagonizing eNOS via b2GPI and apoER2

Sangeetha Ramesh, et al. J. Clin. Invest. 2011; 121(1):120-131

Speaker: Yi-Wen Yang (楊逸紋)                                            Time: 15:10~16:00, Mar. 14, 2012

Commentator: Dr. Bei-Chang Yang (楊倍昌博士)        Place: Room 601

Abstract:

The binding of antiphospholipid antibodies (aPL) to b2 glycoprotein I (b2GPI) on endothelial cells and platelets can promote leukocyte-endothelial cell interaction and thrombus formation (1). The mechanism of aPL-mediated leukocyte-endothelail cell interaction is not clear. Previous studies indicated that NO plays a key role in vascular functions, including leukocyte-endothelial cell interaction and thrombus formation (2). In the present study, the authors demonstrated that aPL could decrease NO production by antagonizing eNOS and increase leukocyte-endothelial cell interaction in vitro. Furthermore, aPL reduced the stimulation of acetylcholine-mediated increases in vascular conductance in vivo. They also showed that the binding of aPL to domain I of b2GPI and b2GPI dimerization blunted eNOS S1179 phosphorylation and activation by protein phosphatase 2A (PP2A). Studies in the inhibition of receptor-associated protein (RAP) and ApoER2^-/- mice both showed that the interaction between apoER2 and b2GPI is important for eNOS antagonized by aPL. Finally, aPL-induced leukocyte-endothelial cell interaction and thrombus formation could not be observed in eNOS^-/- and ApoER2^-/- mice. In conclusion, aPL promotes leukocyte-endothelial cell interaction and thrombus formation through binding to b2GPI and inhibiting eNOS activity. These findings implicate a new therapy which directly targets the pathological mechanism of antiphospholipid syndrome.

Reference:

1.       Panayiotis G. Vlachoyiannopoulos and John G. Routsias. A novel mechanism of thrombosis in antiphospholipid antibody syndrome. J. Autoimmun. 2010; 35(3):248-255.

2.       Barbara Voetsch, Richard C. Jin and Joseph Loscalzo. Nitric oxide insufficiency and atherothrombosis. Histochem. Cell Biol. 2004; 122(4):353–367.