Lysophosphatidic acid mediates the rapid activation of platelets and endothelial cells by mildly oxidized low density lipoprotein and accumulates in human atherosclerotic lesions

Wolfgang Siess, Konrad J. Zangl, Markus Essler, Markus Bauer, Richard Brandl, Carolin Corrinth, Robert Bittman, Gabor Tigyi, Martin Aepfelbacher

Research output: Contribution to journalArticle

333 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)6931-6936
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume96
Issue number12
DOIs
StatePublished - Jun 8 1999

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Platelet Activation
Endothelial Cells
Blood Platelets
LDL Lipoproteins
Atherosclerosis
Lysophosphatidic Acid Receptors
Lipids
Stress Fibers
Atherosclerotic Plaques
Cell Wall
Rupture
Stroke
Myocardial Infarction
lysophosphatidic acid
oxidized low density lipoprotein

All Science Journal Classification (ASJC) codes

  • General

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Lysophosphatidic acid mediates the rapid activation of platelets and endothelial cells by mildly oxidized low density lipoprotein and accumulates in human atherosclerotic lesions. / Siess, Wolfgang; Zangl, Konrad J.; Essler, Markus; Bauer, Markus; Brandl, Richard; Corrinth, Carolin; Bittman, Robert; Tigyi, Gabor; Aepfelbacher, Martin.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 96, No. 12, 08.06.1999, p. 6931-6936.

Research output: Contribution to journalArticle

Siess, Wolfgang ; Zangl, Konrad J. ; Essler, Markus ; Bauer, Markus ; Brandl, Richard ; Corrinth, Carolin ; Bittman, Robert ; Tigyi, Gabor ; Aepfelbacher, Martin. / Lysophosphatidic acid mediates the rapid activation of platelets and endothelial cells by mildly oxidized low density lipoprotein and accumulates in human atherosclerotic lesions. In: Proceedings of the National Academy of Sciences of the United States of America. 1999 ; Vol. 96, No. 12. pp. 6931-6936.
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AU - Siess, Wolfgang

AU - Zangl, Konrad J.

AU - Essler, Markus

AU - Bauer, Markus

AU - Brandl, Richard

AU - Corrinth, Carolin

AU - Bittman, Robert

AU - Tigyi, Gabor

AU - Aepfelbacher, Martin

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N2 - 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.

AB - 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.

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