Document Detail

Lipoprotein-associated phospholipase A2 as a target of therapy.
MedLine Citation:
PMID:  15990594     Owner:  NLM     Status:  MEDLINE    
PURPOSE OF REVIEW: Considerable discussion continues regarding the precise role that secreted lipoprotein-associated phospholipase A2 (Lp-PLA2), also called platelet-activating factor acetylhydrolase, plays in atherosclerosis. Since interest in this enzyme as a putative drug target has been based primarily upon its association with low-density lipoprotein (LDL) in human plasma, this review will focus on Lp-PLA2 and human coronary heart disease. RECENT FINDINGS: Recent reports have linked Lp-PLA2 enrichment not only to the most atherogenic of LDL particles but also to the most advanced, rupture-prone, plaques. Electronegative LDL has been shown to be highly enriched in Lp-PLA2; and in advanced atheroma, Lp-PLA2 levels are highly upregulated, colocalizing with macrophages in both the necrotic core and fibrous cap. Lp-PLA2 is well placed, whether on an oxidation susceptible LDL particle or in the highly oxidative environment of an advanced rupture-prone plaque, to hydrolyse oxidized phospholipid and generate significant quantities of the two pro-inflammatory mediators, lysophosphatidylcholine and oxidized nonesterified fatty acid. Several studies have confirmed that Lp-PLA2 is an independent risk factor for cardiovascular events (i.e. myocardial infarction and stroke). Although epidemiology studies consistently support a relationship between plasma Lp-PLA2 levels and susceptibility to coronary heart disease this is not the case for Lp-PLA2 polymorphisms. Two clinical studies have linked the Ala-379-->Val polymorphism with a reduced risk of myocardial infarction, but functional differences between the AA and VV polymorphs have yet to be demonstrated. SUMMARY: Lp-PLA2 is intimately associated with several aspects of human atherogenesis. Although various lipid-lowering therapies, such as statins, have been shown to reduce plasma levels of Lp-PLA2, none has been studied in terms of its ability to lower the large macrophage-mediated upregulation of Lp-PLA2 within advanced plaques.
Colin H Macphee; Jeanenne J Nelson; Andrew Zalewski
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Publication Detail:
Type:  Journal Article; Review    
Journal Detail:
Title:  Current opinion in lipidology     Volume:  16     ISSN:  0957-9672     ISO Abbreviation:  Curr. Opin. Lipidol.     Publication Date:  2005 Aug 
Date Detail:
Created Date:  2005-07-01     Completed Date:  2005-10-20     Revised Date:  2007-11-15    
Medline Journal Info:
Nlm Unique ID:  9010000     Medline TA:  Curr Opin Lipidol     Country:  England    
Other Details:
Languages:  eng     Pagination:  442-6     Citation Subset:  IM    
Department of Vascular Biology and Thrombosis, GlaxoSmithKline, King of Prussia, PA 19406, USA.
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MeSH Terms
1-Alkyl-2-acetylglycerophosphocholine Esterase
Cardiovascular Diseases / drug therapy*,  enzymology*,  etiology
Lovastatin / therapeutic use
Macrophages / enzymology
Phospholipases A / antagonists & inhibitors,  genetics,  metabolism*
Phospholipases A2
Reg. No./Substance:
75330-75-5/Lovastatin; EC 3.1.1.-/Phospholipases A; EC A2; EC Esterase

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