Lipoprotein-associated phospholipase A2 as a target of therapy.
OBJECTIVE
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.


RESULTS
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.


CONCLUSIONS
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.
Macphee
Colin H
CH
Department of Vascular Biology and Thrombosis, GlaxoSmithKline, King of Prussia, PA 19406, USA. colin_h_macphee@gsk.com
Nelson
Jeanenne J
JJ
Zalewski
Andrew
A
D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; D002318:Cardiovascular Diseases / Q000188:drug therapy* / Q000201:enzymology* / Q000209:etiology; D006801:Humans; D008148:Lovastatin / Q000627:therapeutic use; D008264:Macrophages / Q000201:enzymology; D010741:Phospholipases A / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D054467:Phospholipases A2
D008148:Lovastatin; D010741:Phospholipases A; D054467:Phospholipases A2; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase