Lysophosphatidic acid mediates the rapid activation of platelets and endothelial cells by mildly oxidized low density lipoprotein and accumulates in human atherosclerotic lesions
W. Siess et al., Lysophosphatidic acid mediates the rapid activation of platelets and endothelial cells by mildly oxidized low density lipoprotein and accumulates in human atherosclerotic lesions, P NAS US, 96(12), 1999, pp. 6931-6936
Citations number
35
Categorie Soggetti
Multidisciplinary
Journal title
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Oxidized low density lipoprotein (LDL) is a key factor in the pathogenesis
of atherosclerosis and its thrombotic complications, such as stroke and myo
cardial infarction, It activates endothelial cells and platelets through me
chanisms 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 acti
vation and stimulating endothelial cell stress-fiber and gap formation. Ant
agonists of the LPA receptor prevented platelet and endothelial cell activa
tion 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 highe
st in the lipid-rich core, the region most thrombogenic and most prone to r
upture. Given the potent biological activity of LPA on platelets and on cel
ls of the vessel wall, our study identifies LPA as an atherothrombogenic mo
lecule and suggests a possible strategy to prevent and treat atherosclerosi
s and cardiocerebrovascular diseases.