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 Mills, Andrew J. Morris, Susan S. Smyth

Research output: Contribution to journalArticle

97 Citations (Scopus)

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
Externally publishedYes

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Hemostasis
Thrombosis
Platelets
Blood Platelets
4 alpha-glucanotransferase
Plasmas
lysophosphatidic acid
Agglomeration
Bleeding Time
Disease Susceptibility
Platelet Aggregation
Integrins
Blood Vessels
Hemorrhage
Lipids

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Pamuklar, Z., Federico, L., Liu, S., Umezu-Goto, M., Dong, A., Panchatcharam, M., ... 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

Autotaxin/Lysopholipase D and lysophosphatidic acid regulate murine hemostasis and thrombosis. / Pamuklar, Zehra; Federico, Lorenzo; Liu, Shuying; Umezu-Goto, Makiko; Dong, Anping; Panchatcharam, Manikandan; Fulerson, Zachary; Berdyshev, Evgeny; Natarajan, Viswanathan; Fang, Xianjun; van Meeteren, Laurens A.; Moolenaar, Wouter H.; Mills, Gordon; Morris, Andrew J.; Smyth, Susan S.

In: Journal of Biological Chemistry, Vol. 284, No. 11, 13.03.2009, p. 7385-7394.

Research output: Contribution to journalArticle

Pamuklar, Z, Federico, L, Liu, S, Umezu-Goto, M, Dong, A, Panchatcharam, M, Fulerson, Z, Berdyshev, E, Natarajan, V, Fang, X, van Meeteren, LA, Moolenaar, WH, Mills, G, Morris, AJ & Smyth, SS 2009, 'Autotaxin/Lysopholipase D and lysophosphatidic acid regulate murine hemostasis and thrombosis', Journal of Biological Chemistry, vol. 284, no. 11, pp. 7385-7394. https://doi.org/10.1074/jbc.M807820200
Pamuklar Z, Federico L, Liu S, Umezu-Goto M, Dong A, Panchatcharam M et al. Autotaxin/Lysopholipase D and lysophosphatidic acid regulate murine hemostasis and thrombosis. Journal of Biological Chemistry. 2009 Mar 13;284(11):7385-7394. https://doi.org/10.1074/jbc.M807820200
Pamuklar, Zehra ; Federico, Lorenzo ; Liu, Shuying ; Umezu-Goto, Makiko ; Dong, Anping ; Panchatcharam, Manikandan ; Fulerson, Zachary ; Berdyshev, Evgeny ; Natarajan, Viswanathan ; Fang, Xianjun ; van Meeteren, Laurens A. ; Moolenaar, Wouter H. ; Mills, Gordon ; Morris, Andrew J. ; Smyth, Susan S. / Autotaxin/Lysopholipase D and lysophosphatidic acid regulate murine hemostasis and thrombosis. In: Journal of Biological Chemistry. 2009 ; Vol. 284, No. 11. pp. 7385-7394.
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