Antiphospholipid antibodies promote leukocyte-endothelial cell adhesion and thrombosis in mice by antagonizing eNOS via β2GPI and apoER2

Sangeetha Ramesh, Craig N. Morrell, Cristina Tarango, Gail D. Thomas, Ivan S. Yuhanna, Guillermina Girardi, Joachim Herz, Rolf T. Urbanus, Philip G. De Groot, Philip E. Thorpe, Jane E. Salmon, Philip W. Shaul, Chieko Mineo

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Abstract

In antiphospholipid syndrome (APS), antiphospholipid antibodies (aPL) binding to β2 glycoprotein I (β2GPI) induce endothelial cell-leukocyte adhesion and thrombus formation via unknown mechanisms. Here we show that in mice both of these processes are caused by the inhibition of eNOS. In studies of cultured human, bovine, and mouse endothelial cells, the promotion of monocyte adhesion by aPL entailed decreased bioavailable NO, and aPL fully antagonized eNOS activation by diverse agonists. Similarly, NO-dependent, acetylcholine-induced increases in carotid vascular conductance were impaired in aPL-treated mice. The inhibition of eNOS was caused by antibody recognition of domain I of β2GPI and β2GPI dimerization, and it was due to attenuated eNOS S1179 phosphorylation mediated by protein phosphatase 2A (PP2A). Furthermore, LDL receptor family member antagonism with receptor-associated protein (RAP) prevented aPL inhibition of eNOS in cell culture, and ApoER2-/- mice were protected from aPL inhibition of eNOS in vivo. Moreover, both aPL-induced increases in leukocyte-endothelial cell adhesion and thrombus formation were absent in eNOS-/-and in ApoER2-/- mice. Thus, aPL-induced leukocyte-endothelial cell adhesion and thrombosis are caused by eNOS antagonism, which is due to impaired S1179 phosphorylation mediated by β2GPI, apoER2, and PP2A. Our results suggest that novel therapies for APS can now be developed targeting these mechanisms.

Original languageEnglish (US)
Pages (from-to)120-131
Number of pages12
JournalJournal of Clinical Investigation
Volume121
Issue number1
DOIs
StatePublished - Jan 4 2011

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Antiphospholipid Antibodies
Cell Adhesion
Glycoproteins
Thrombosis
Leukocytes
Endothelial Cells
Protein Phosphatase 2
Antiphospholipid Syndrome
Phosphorylation
LDL Receptors
Dimerization
Acetylcholine
Blood Vessels
Monocytes
Cell Culture Techniques
Inhibition (Psychology)
Antibodies

ASJC Scopus subject areas

  • Medicine(all)

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Antiphospholipid antibodies promote leukocyte-endothelial cell adhesion and thrombosis in mice by antagonizing eNOS via β2GPI and apoER2. / Ramesh, Sangeetha; Morrell, Craig N.; Tarango, Cristina; Thomas, Gail D.; Yuhanna, Ivan S.; Girardi, Guillermina; Herz, Joachim; Urbanus, Rolf T.; De Groot, Philip G.; Thorpe, Philip E.; Salmon, Jane E.; Shaul, Philip W.; Mineo, Chieko.

In: Journal of Clinical Investigation, Vol. 121, No. 1, 04.01.2011, p. 120-131.

Research output: Contribution to journalArticle

Ramesh, S, Morrell, CN, Tarango, C, Thomas, GD, Yuhanna, IS, Girardi, G, Herz, J, Urbanus, RT, De Groot, PG, Thorpe, PE, Salmon, JE, Shaul, PW & Mineo, C 2011, 'Antiphospholipid antibodies promote leukocyte-endothelial cell adhesion and thrombosis in mice by antagonizing eNOS via β2GPI and apoER2', Journal of Clinical Investigation, vol. 121, no. 1, pp. 120-131. https://doi.org/10.1172/JCI39828
Ramesh, Sangeetha ; Morrell, Craig N. ; Tarango, Cristina ; Thomas, Gail D. ; Yuhanna, Ivan S. ; Girardi, Guillermina ; Herz, Joachim ; Urbanus, Rolf T. ; De Groot, Philip G. ; Thorpe, Philip E. ; Salmon, Jane E. ; Shaul, Philip W. ; Mineo, Chieko. / Antiphospholipid antibodies promote leukocyte-endothelial cell adhesion and thrombosis in mice by antagonizing eNOS via β2GPI and apoER2. In: Journal of Clinical Investigation. 2011 ; Vol. 121, No. 1. pp. 120-131.
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AU - Thomas, Gail D.

AU - Yuhanna, Ivan S.

AU - Girardi, Guillermina

AU - Herz, Joachim

AU - Urbanus, Rolf T.

AU - De Groot, Philip G.

AU - Thorpe, Philip E.

AU - Salmon, Jane E.

AU - Shaul, Philip W.

AU - Mineo, Chieko

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