Multiple mechanisms linked to platelet activation result in lysophosphatidic acid and sphingosine 1-phosphate generation in blood

被引:220
作者
Sano, T
Baker, D
Virag, T
Wada, A
Yatomi, Y
Kobayashi, T
Igarashi, Y
Tigyi, G
机构
[1] Univ Tennessee, Ctr Hlth Sci, Dept Physiol, Memphis, TN 38163 USA
[2] Hokkaido Univ, Grad Sch Pharmaceut Sci, Dept Biomembrane & Biofunct Chem, Sapporo, Hokkaido 060812, Japan
[3] Yamanashi Med Univ, Dept Lab Med, Yamanashi 4093898, Japan
[4] Ochanomizu Univ, Dept Biol, Tokyo 112, Japan
关键词
D O I
10.1074/jbc.M201289200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Lysophosphatidic acid (LPA) and sphingosine 1-phosphate (Sph1P) production was examined in vitro under conditions that simulated blood clotting. Several approaches were utilized to elucidate the metabolic pathways. 1) Platelet phospholipids were labeled using [P-32]orthophosphate, and the production of [P-32]Sph1P and LPA was examined. Thrombin stimulation of platelets resulted in rapid secretion of Sph1P stored within the platelet. In contrast, LPA was neither stored within nor secreted from platelets. Nonetheless, extracellular levels of LPA gradually increased following stimulation. 2) Stable-isotope dilution mass spectrometry was used to quantify the molecular species of LPA generated from platelets in vitro. Only 10% of the LPA generated following thrombin stimulation was associated with platelets, the remaining 90% was contained within the extracellular medium. The acyl composition of LPA produced by platelets differed depending on the presence or absence of plasma in the incubation. 3) The fate of exogenously added fluorescent phospholipid analogs was determined. Incubation of [(7-nitro-2-1,3-benzoxadiazol-4-yl)amino]dodecanoyl-(NDD) -labeled phosphatidylcholine, phosphatidylethanolamine, and phosphatidylserine with the supernatant fractions from thrombin-stimulated platelets yielded no LPA production. However, these lipids were converted to the corresponding lysolipids by released PLA(1) and PLA(2) activities. When incubated with plasma or serum the NBD-labeled lysophospholipids were readily converted to LPA. Inhibitors of lysophospholipase D and the biological activity of LPA were detected in plasma. These results suggest that the bulk of LPA produced through platelet activation results from the sequential cleavage of phospholipids to lysophospholipids by released phospholipases A(1) and A(2) and then to LPA by plasma lysophospholipase D.
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收藏
页码:21197 / 21206
页数:10
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