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.


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.
Rother
Enno
E
Institute for Prevention of Cardiovascular Diseases, Medical Faculty, University Munich, Germany.
Brandl
Richard
R
Baker
Daniel L
DL
Goyal
Pankaj
P
Gebhard
Harry
H
Tigyi
Gabor
G
Siess
Wolfgang
W
D000244:Adenosine Diphosphate / Q000037:antagonists & inhibitors / Q000494:pharmacology; D001161:Arteriosclerosis / Q000473:pathology / Q000503:physiopathology*; D001681:Biological Assay; D001792:Blood Platelets / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002469:Cell Separation; D048429:Cell Size / Q000187:drug effects; D002853:Chromatography, Liquid; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004837:Epinephrine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D006801:Humans; D008055:Lipids / Q000302:isolation & purification / Q000494:pharmacology*; D008246:Lysophospholipids / Q000037:antagonists & inhibitors / Q000494:pharmacology; D013058:Mass Spectrometry; D009943:Organophosphorus Compounds / Q000494:pharmacology*; D010712:Phosphatidic Acids / Q000494:pharmacology*; D015539:Platelet Activation / Q000187:drug effects*; D010974:Platelet Aggregation / Q000187:drug effects; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors*; D043562:Receptors, G-Protein-Coupled; D049368:Receptors, Lysophosphatidic Acid
D008055:Lipids; D008246:Lysophospholipids; D009943:Organophosphorus Compounds; D010712:Phosphatidic Acids; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D049368:Receptors, Lysophosphatidic Acid; D000244:Adenosine Diphosphate; D004837:Epinephrine