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Evidence supporting a key role of Lp-PLA2-generated lysophosphatidylcholine in human atherosclerotic plaque inflammation.
Arterioscler. Thromb. Vasc. Biol. 32, 1505-1512 (2012)
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 lysoPC 16:0, 18:0, 18:1, LPA, and Lp-PLA2 in plaques. LysoPC 16:0, 18:0, 18:1, LPA, and Lp-PLA2 correlated with interleukin-1β, interleukin-6, monocyte chemoattractant protein-1, macrophage inflammatory protein-1β, regulated on activation normal T-cell expressed and secreted, and tumor necrosis factor-α 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 were higher in symptomatic than in asymptomatic plaques. CONCLUSIONS: The associations among Lp-PLA2, lysoPCs, LPA, and proinflammatory cytokines in human plaques suggest that lysoPCs play a key role in plaque inflammation and vulnerability. Our findings support Lp-PLA2 inhibition as a possible strategy for the prevention of cardiovascular disease.
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Publikationstyp
Artikel: Journalartikel
Dokumenttyp
Wissenschaftlicher Artikel
Schlagwörter
atherosclerosis; carotid plaque; inflammation; lipoprotein-associated phospholipase A2; lysophosphatidylcholine; LOW-DENSITY-LIPOPROTEIN; SMOOTH-MUSCLE-CELLS; CORONARY-ARTERY-DISEASE; HUMAN ENDOTHELIAL-CELLS; PHOSPHOLIPASE A(2); DEPENDENT MECHANISM; HUMAN-MONOCYTES; T-LYMPHOCYTES; OXIDIZED LDL; EXPRESSION
ISSN (print) / ISBN
1079-5642
e-ISSN
1524-4636
Quellenangaben
Band: 32,
Heft: 6,
Seiten: 1505-1512
Verlag
Lippincott Williams & Wilkins
Nichtpatentliteratur
Publikationen
Begutachtungsstatus
Peer reviewed
Institut(e)
Molekulare Endokrinologie und Metabolismus (MEM)
Institute of Experimental Genetics (IEG)
Institute of Experimental Genetics (IEG)