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 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.