Lysophosphatidic Acid Mediates the Rapid Activation of Platelets and Endothelial Cells by Mildly Oxidized Low Density Lipoprotein and Accumulates in Human Atherosclerotic Lesions

Oxidized low density lipoprotein (LDL) is a key factor in the pathogenesis of atherosclerosis and its thrombotic complications, such as stroke and myocardial infarction. It activates endothelial cells and platelets through mechanisms that are largely unknown. Here, we show that lysophosphatidic acid...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 1999-06, Vol.96 (12), p.6931-6936
Main Authors: Siess, Wolfgang, Zangl, Konrad J., Essler, Markus, Bauer, Markus, Brandl, Richard, Corrinth, Carolin, Bittman, Robert, Tigyi, Gabor, Aepfelbacher, Martin
Format: Article
Language:English
Subjects:
Actins
Arteriosclerosis - metabolism
Arteriosclerosis - physiopathology
Atherosclerosis
Biological Sciences
Blood Platelets - physiology
Cells, Cultured
Endothelial cells
Endothelium, Vascular - physiopathology
Fatty acids
Humans
Lesions
Lipids
Lipoproteins
Lipoproteins, LDL - metabolism
Lysophospholipids
Lysophospholipids - metabolism
Molecules
Oxidation
Platelet Activation
Platelets
Proteins
Specimens
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Summary:Oxidized low density lipoprotein (LDL) is a key factor in the pathogenesis of atherosclerosis and its thrombotic complications, such as stroke and myocardial infarction. It activates endothelial cells and platelets through mechanisms that are largely unknown. Here, we show that lysophosphatidic acid (LPA) was formed during mild oxidation of LDL and was the active compound in mildly oxidized LDL and minimally modified LDL, initiating platelet activation and stimulating endothelial cell stress-fiber and gap formation. Antagonists of the LPA receptor prevented platelet and endothelial cell activation by mildly oxidized LDL. We also found that LPA accumulated in and was the primary platelet-activating lipid of atherosclerotic plaques. Notably, the amount of LPA within the human carotid atherosclerotic lesion was highest in the lipid-rich core, the region most thrombogenic and most prone to rupture. Given the potent biological activity of LPA on platelets and on cells of the vessel wall, our study identifies LPA as an atherothrombogenic molecule and suggests a possible strategy to prevent and treat atherosclerosis and cardiocerebrovascular diseases.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.96.12.6931