Subtype-selective antagonists of lysophosphatidic acid receptors inhibit platelet activation triggered by the lipid core of atherosclerotic plaques

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 LPA(1) and LPA(3) 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 LPA(1) and LPA(3) receptors. Antagonists of platelet LPA receptors might provide a new strategy to prevent thrombus formation in patients with cardiovascular diseases.