Autotaxin/lysopholipase D and lysophosphatidic acid regulate murine hemostasis and thrombosis.
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 approximately 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.
Pamuklar
Zehra
Z
Division of Cardiovascular Medicine, The Gill Heart Institute, Lexington, Kentucky 40536-0200, USA.
Federico
Lorenzo
L
Liu
Shuying
S
Umezu-Goto
Makiko
M
Dong
Anping
A
Panchatcharam
Manikandan
M
Fulkerson
Zachary
Z
Fulerson
Zachary
Z
Berdyshev
Evgeny
E
Natarajan
Viswanathan
V
Fang
Xianjun
X
van Meeteren
Laurens A
LA
Moolenaar
Wouter H
WH
Mills
Gordon B
GB
Morris
Andrew J
AJ
Smyth
Susan S
SS
D000818:Animals; D001792:Blood Platelets / Q000378:metabolism; D006470:Hemorrhage / Q000097:blood / Q000235:genetics; D006487:Hemostasis; D006801:Humans; D008246:Lysophospholipids / Q000097:blood* / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D009097:Multienzyme Complexes / Q000097:blood* / Q000235:genetics; D043264:Phosphodiesterase I / Q000097:blood* / Q000235:genetics; D010727:Phosphoric Diester Hydrolases / Q000097:blood* / Q000235:genetics; D010974:Platelet Aggregation / Q000235:genetics; D011755:Pyrophosphatases / Q000097:blood* / Q000235:genetics; D013927:Thrombosis / Q000097:blood* / Q000235:genetics; D000099189:Lysophospholipase D
D008246:Lysophospholipids; D009097:Multienzyme Complexes; D043264:Phosphodiesterase I; D010727:Phosphoric Diester Hydrolases; D011755:Pyrophosphatases; D000099189:Lysophospholipase D; C032881:lysophosphatidic acid