TY - JOUR
T1 - Autotaxin/Lysopholipase D and lysophosphatidic acid regulate murine hemostasis and thrombosis
AU - Pamuklar, Zehra
AU - Federico, Lorenzo
AU - Liu, Shuying
AU - Umezu-Goto, Makiko
AU - Dong, Anping
AU - Panchatcharam, Manikandan
AU - Fulerson, Zachary
AU - Berdyshev, Evgeny
AU - Natarajan, Viswanathan
AU - Fang, Xianjun
AU - van Meeteren, Laurens A.
AU - Moolenaar, Wouter H.
AU - Mills, Gordon B.
AU - Morris, Andrew J.
AU - Smyth, Susan S.
PY - 2009/3/13
Y1 - 2009/3/13
N2 - The lipid mediator lysophosphatidic acid (LPA) is a potent regulator of vascular cell function in vitro, but its physiologic role in the cardiovasculature is largely unexplored. To address the role of LPA in regulating platelet function and thrombosis, we investigated the effects of LPA on isolated murine platelets. Although LPA activates platelets from the majority of human donors, we found that treatment of isolated murine platelets with physiologic concentrations of LPA attenuated agonist-induced aggregation. Transgenic overexpression of autotaxin/ lysophospholipase D (Enpp2), the enzyme necessary for production of the bulk of biologically active LPA in plasma, elevated circulating LPA levels and induced a bleeding diathesis and attenuation of thrombosis in mice. Intravascular administration of exogenous LPA recapitulated the prolonged bleeding time observed in Enpp2-Tg mice. Enpp2+/- mice, which have ∼50%normal plasma LPA levels, were more prone to thrombosis. Plasma autotaxin associated with platelets during aggregation and concentrated in arterial thrombus, and activated but not resting platelets bound recombinant autotaxin/lysoPLD in an integrin-dependent manner. These results identify a novel pathway in which LPA production by autotaxin/lysoPLD regulates murine hemostasis and thrombosis and suggest that binding of autotaxin/lysoPLD to activated platelets may provide a mechanism to localize LPA production.
AB - The lipid mediator lysophosphatidic acid (LPA) is a potent regulator of vascular cell function in vitro, but its physiologic role in the cardiovasculature is largely unexplored. To address the role of LPA in regulating platelet function and thrombosis, we investigated the effects of LPA on isolated murine platelets. Although LPA activates platelets from the majority of human donors, we found that treatment of isolated murine platelets with physiologic concentrations of LPA attenuated agonist-induced aggregation. Transgenic overexpression of autotaxin/ lysophospholipase D (Enpp2), the enzyme necessary for production of the bulk of biologically active LPA in plasma, elevated circulating LPA levels and induced a bleeding diathesis and attenuation of thrombosis in mice. Intravascular administration of exogenous LPA recapitulated the prolonged bleeding time observed in Enpp2-Tg mice. Enpp2+/- mice, which have ∼50%normal plasma LPA levels, were more prone to thrombosis. Plasma autotaxin associated with platelets during aggregation and concentrated in arterial thrombus, and activated but not resting platelets bound recombinant autotaxin/lysoPLD in an integrin-dependent manner. These results identify a novel pathway in which LPA production by autotaxin/lysoPLD regulates murine hemostasis and thrombosis and suggest that binding of autotaxin/lysoPLD to activated platelets may provide a mechanism to localize LPA production.
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U2 - 10.1074/jbc.M807820200
DO - 10.1074/jbc.M807820200
M3 - Article
C2 - 19139100
AN - SCOPUS:65449156892
SN - 0021-9258
VL - 284
SP - 7385
EP - 7394
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 11
ER -