Autotaxin/Lysopholipase D and lysophosphatidic acid regulate murine hemostasis and thrombosis

Zehra Pamuklar, Lorenzo Federico, Shuying Liu, Makiko Umezu-Goto, Anping Dong, Manikandan Panchatcharam, Zachary Fulerson, Evgeny Berdyshev, Viswanathan Natarajan, Xianjun Fang, Laurens A. van Meeteren, Wouter H. Moolenaar, Gordon B. Mills, Andrew J. Morris, Susan S. Smyth

    Research output: Contribution to journalArticle

    106 Scopus citations

    Abstract

    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.

    Original languageEnglish (US)
    Pages (from-to)7385-7394
    Number of pages10
    JournalJournal of Biological Chemistry
    Volume284
    Issue number11
    DOIs
    StatePublished - Mar 13 2009

    ASJC Scopus subject areas

    • Biochemistry
    • Molecular Biology
    • Cell Biology

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  • Cite this

    Pamuklar, Z., Federico, L., Liu, S., Umezu-Goto, M., Dong, A., Panchatcharam, M., Fulerson, Z., Berdyshev, E., Natarajan, V., Fang, X., van Meeteren, L. A., Moolenaar, W. H., Mills, G. B., Morris, A. J., & Smyth, S. S. (2009). Autotaxin/Lysopholipase D and lysophosphatidic acid regulate murine hemostasis and thrombosis. Journal of Biological Chemistry, 284(11), 7385-7394. https://doi.org/10.1074/jbc.M807820200