title: The class I phosphoinositide 3-kinases α and β control antiphospholipid antibodies-induced platelet activation.
abstract: Antiphospholipid syndrome (APS) is an autoimmune disease characterised by the presence of antiphospholipid antibodies (aPL) associated with increased thrombotic risk and pregnancy morbidity. Although aPL are heterogeneous auto-antibodies, the major pathogenic target is the plasma protein β2-glycoprotein 1. The molecular mechanisms of platelet activation by aPL remain poorly understood. Here, we explored the role of the class IA phosphoinositide 3-kinase (PI3K) α and β isoforms in platelet activation by aPL. Compared to control IgG from healthy individuals, the IgG fraction isolated from patients with APS potentiates platelet aggregation induced by low dose of thrombin in vitro and increases platelet adhesion and thrombus growth on a collagen matrix under arterial shear rate through a mechanism involving glycoprotein Ib (GPIb) and Toll Like Receptor 2 (TLR-2). Using isoforms-selective pharmacological PI3K inhibitors and mice with megakaryocyte/platelet lineage-specific inactivation of class IA PI3K isoforms, we demonstrate a critical role of the PI3Kβ and PI3Kα isoforms in platelet activation induced by aPL. Our data show that aPL potentiate platelet activation through GPIbα and TLR-2 via a mechanism involving the class IA PI3Kα and β isoforms, which represent new potential therapeutic targets in the prevention or treatment of thrombotic events in patients with APS.
authors.affiliation: Anne-Dominique Terrisse, Inserm U1048, I2MC, 1 Avenue Jean Poulhés, BP 84225, 31432 Toulouse Cedex 04, France, Tel.: +33 5 3122 4150, Fax: +33 5 6132 5621, E-mail: anne-dominique.terrisse@inserm.fr.
authors.forename: Anne-Dominique
authors.initials: AD
authors.lastname: Terrisse
authors.forename: Pierre-Alexandre
authors.initials: PA
authors.lastname: Laurent
authors.forename: Cédric
authors.initials: C
authors.lastname: Garcia
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: Gratacap
authors.forename: Bart
authors.initials: B
authors.lastname: Vanhaesebroeck
authors.forename: Pierre
authors.initials: P
authors.lastname: Sié
authors.forename: Bernard
authors.initials: B
authors.lastname: Payrastre
mesh_terms: D000818:Animals; D017152:Antibodies, Antiphospholipid / Q000097:blood*; D016736:Antiphospholipid Syndrome / Q000097:blood* / Q000276:immunology*; D016022:Case-Control Studies; D058534:Class I Phosphatidylinositol 3-Kinases / Q000097:blood / Q000172:deficiency / Q000235:genetics; D058543:Class Ia Phosphatidylinositol 3-Kinase / Q000097:blood*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood; D066298:In Vitro Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000081082:Phosphoinositide-3 Kinase Inhibitors; D015539:Platelet Activation / Q000276:immunology*; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000378:metabolism; D013927:Thrombosis / Q000097:blood / Q000209:etiology / Q000276:immunology; D051195:Toll-Like Receptor 2 / Q000097:blood
chemical_list: D017152:Antibodies, Antiphospholipid; D004791:Enzyme Inhibitors; D007074:Immunoglobulin G; D000081082:Phosphoinositide-3 Kinase Inhibitors; D019038:Platelet Glycoprotein GPIb-IX Complex; C495342:TLR2 protein, human; D051195:Toll-Like Receptor 2; C509622:1-phosphatidylinositol 3-kinase p110 subunit, mouse; D058534:Class I Phosphatidylinositol 3-Kinases; D058543:Class Ia Phosphatidylinositol 3-Kinase
keywords: Antiphospholipid antibodies; blood platelets; phosphoinositide 3-kinases; thrombosis