lysophosphatidylcholine in Human Atherosclerotic Plaque inflammation

A rterial inflammation is the principal driving force responsible for atherosclerotic plaque development and destabilization. There is strong evidence that this inflammation is induced by the retention and oxidation of low-density lipo-protein (LDL) in the subendothelial space. Oxidized LDL is cytotoxic and may induce inflammation by causing arterial cell injury and by recruiting oxidized LDL-specific proinflam-matory T cells to the artery wall. 3 It has also been proposed that oxidized LDL may activate inflammation directly through interaction with macrophage Toll-like receptors. 4 An alternative pathway through which oxidized LDL may initiate inflammation is through the release of bioactive metabolites. Oxidized phospholipids in LDL are hydrolyzed by lipopro-tein-associated phospholipase A2 (Lp-PLA2) to generate lysophosphatidylcholines (lysoPCs) and oxidized nonesterified fatty acids. 5 LysoPCs have been shown to be a potent chemoat-tractant for T-cells and monocytes, 6,7 promote endothelial dysfunction, 8 induce release of arachidonic acid, 9 and induce apoptosis of endothelial and vascular smooth muscle cells. These in vitro observations imply that lysoPCs may contribute to the development of atherosclerotic plaques as well as to plaque vulnerability and rupture. This hypothesis is also supported by studies showing that the Lp-PLA2 and lysoPCs content of human carotid plaques predict future cardiovascular events and that Lp-PLA2 and lysoPC's plaque expression are increased in symptomatic human carotid plaques. Plasma levels of Lp-PLA2 and its activity have also been shown to be independent predictors of cardiovascular risk in several Objective—To determine whether the level of lysophosphatidylcholine (lysoPC) generated by lipoprotein-associated phospholipase A2 (Lp-PLA2) is associated with severity of inflammation in human atherosclerotic plaques. Elevated plasma Lp-PLA2 is associated with increased cardiovascular risk. Lp-PLA2 inhibition reduces atherosclerosis. Lp-PLA2 hydrolyzes low-density lipoprotein–oxidized phospholipids generating lysoPCs. According to in vitro studies, lysoPCs are proinflammatory but the association between their generation and plaque inflammation remains unknown. Methods and Results—Inflammatory activity in carotid plaques (162 patients) was determined immunohistochemically and by analyzing cytokines in homogenates (multiplex immunoassay). LysoPCs were quantified using mass spectrometry and Lp-PLA2 and the lysoPC metabolite lysophosphatidic acid (LPA) by ELISA. There was a strong correlation among and Lp-PLA2 correlated with interleukin-1, interleukin-6, monocyte chemoattractant protein-1, macrophage inflammatory protein-1, regulated on activation normal T-cell expressed and secreted, and tumor necrosis factor- in plaques. High lysoPC and Lp-PLA2 correlated with increased plaque macrophages and lipids and with low content of smooth muscle cells, whereas LPA only correlated with plaque macrophages. Lp-PLA2, lysoPC 16:0, 18:0, and 18:1, but not LPA …