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(Circulation. 2003;108:741.)
© 2003 American Heart Association, Inc.

Basic Science Reports

Subtype-Selective Antagonists of Lysophosphatidic Acid Receptors Inhibit Platelet Activation Triggered by the Lipid Core of Atherosclerotic Plaques

Enno Rother, BS; Richard Brandl, MD; Daniel L. Baker, PhD; Pankaj Goyal, MSc; Harry Gebhard, BS; Gabor Tigyi, MD, PhD; Wolfgang Siess, MD

From the Institute for Prevention of Cardiovascular Diseases, Medical Faculty, University of Munich, Munich, Germany (E.R., P.G., H.G., W.S.); the Department of Vascular Surgery, Klinikum Munich-Schwabing, Munich, Germany (R.B.); and the Department of Physiology, University of Tennessee, Memphis (D.L.B., G.T.).

Correspondence to Dr Wolfgang Siess, Institut für Prophylaxe und Epidemiologie der Kreislaufkrankheiten, Klinikum Innenstadt, Universität München, Pettenkoferstr. 9, D 80336 München, Germany. E-mail wolfgang.siess{at}klp.med.uni-muenchen.de

Received February 24, 2003; revision received April 15, 2003; accepted April 16, 2003.

Background— Lysophosphatidic acid (LPA) is a platelet-activating component of mildly oxidized LDL (mox-LDL) and lipids isolated from human atherosclerotic plaques. Specific antagonists of platelet LPA receptors could be useful inhibitors of thrombus formation in patients with cardiovascular disease.

Methods and Results— Short-chain analogs of phosphatidic acid (PA) were examined for their effect on two initial platelet responses, platelet shape change and Ca²⁺ mobilization. Dioctylglycerol pyrophosphate [DGPP(8:0)] and dioctylphosphatidic acid [PA(8:0)], recently described selective antagonists of the LPA₁ and LPA₃ receptors, inhibited platelet activation evoked by LPA but not by other platelet stimuli. DGPP(8:0) was more potent than PA(8:0). DGPP(8:0) also inhibited platelet shape change induced by mox-LDL and lipid extracts from human atherosclerotic plaques. Notably, we demonstrate for the first time that the lipid-rich core isolated from soft plaques was able to directly induce shape change. This effect was completely abrogated by prior incubation of platelets with DGPP(8:0). Moreover, coapplication of the lipid-rich core or LPA together with subthreshold concentrations of ADP or epinephrine synergistically induced platelet aggregation; this effect was inhibited by DGPP(8:0). Analysis by liquid chromatography-mass spectrometry revealed the presence of LPA alkyl- and acyl-molecular species with high platelet-activating potency (16:0-alkyl-LPA, 20:4-acyl-LPA).

Conclusions— LPA molecules present in the core region of atherosclerotic plaques trigger rapid platelet activation through the stimulation of LPA₁ and LPA₃ receptors. Antagonists of platelet LPA receptors might provide a new strategy to prevent thrombus formation in patients with cardiovascular diseases.

Key Words: platelets • receptors • lipids • plaque • lipoproteins

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