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

Abstract

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.

• Authors: Enno Rother, Richard Brandl, Daniel L Baker, Pankaj Goyal, Harry Gebhard, Gabor Tigyi, Wolfgang Siess
• Journal: Circulation (Circulation) Vol. 108 Issue 6 Pg. 741-7 (Aug 12 2003) ISSN: 1524-4539 [Electronic] United States
• PMID: 12885756 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Lipids
• Lysophospholipids
• Organophosphorus Compounds
• Phosphatidic Acids
• Receptors, Cell Surface
• Receptors, G-Protein-Coupled
• Receptors, Lysophosphatidic Acid
• Adenosine Diphosphate
• Epinephrine

Topics

• Adenosine Diphosphate (antagonists & inhibitors, pharmacology)
• Arteriosclerosis (pathology, physiopathology)
• Biological Assay
• Blood Platelets (cytology, drug effects, metabolism)
• Cell Separation
• Cell Size (drug effects)
• Chromatography, Liquid
• Dose-Response Relationship, Drug
• Drug Synergism
• Epinephrine (antagonists & inhibitors, pharmacology)
• Humans
• Lipids (isolation & purification, pharmacology)
• Lysophospholipids (antagonists & inhibitors, pharmacology)
• Mass Spectrometry
• Organophosphorus Compounds (pharmacology)
• Phosphatidic Acids (pharmacology)
• Platelet Activation (drug effects)
• Platelet Aggregation (drug effects)
• Receptors, Cell Surface (antagonists & inhibitors)
• Receptors, G-Protein-Coupled
• Receptors, Lysophosphatidic Acid