Role of lipoprotein-associated phospholipase A2 in atherosclerosis: biology, epidemiology, and possible therapeutic target.
The development of atherosclerotic vascular disease is invariably linked to the formation of bioactive lipid mediators and accompanying vascular inflammation. Lipoprotein-associated phospholipase A2 (Lp-PLA2) is an enzyme that is produced by inflammatory cells, co-travels with circulating low-density lipoprotein (LDL), and hydrolyzes oxidized phospholipids in LDL. Its biological role has been controversial with initial reports purporting atheroprotective effects of Lp-PLA2 thought to be a consequence of degrading platelet-activating factor and removing polar phospholipids in modified LDL. Recent studies, however, focused on pro-inflammatory role of Lp-PLA2 mediated by products of the Lp-PLA2 reaction (lysophosphatidylcholine and oxidized nonesterified fatty acids). These bioactive lipid mediators, which are generated in lesion-prone vasculature and to a lesser extent in the circulation (eg, in electronegative LDL), are known to elicit several inflammatory responses. The proinflammatory action of Lp-PLA2 is also supported by a number of epidemiology studies suggesting that the circulating level of the enzyme is an independent predictor of cardiovascular events, despite some attenuation of the effect by inclusion of LDL, the primary carrier of Lp-PLA2, in the analysis. These observations provide a rationale to explore whether inhibiting Lp-PLA2 activity and consequent interference with the formation of bioactive lipid mediators will abrogate inflammation associated with atherosclerosis, produce favorable changes in intermediate cardiovascular end points (eg, biomarkers, imaging, and endothelial function), and ultimately reduce cardiovascular events in high-risk patients.
Zalewski
Andrew
A
Medicine Development Centre, GlaxoSmithKline, Philadelphia, Pa, USA. andrew.2.zalewski@gsk.com
Macphee
Colin
C
D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; D000818:Animals; D050197:Atherosclerosis / Q000188:drug therapy / Q000453:epidemiology* / Q000378:metabolism*; D001808:Blood Vessels / Q000201:enzymology* / Q000276:immunology; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D006801:Humans; D010741:Phospholipases A / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D054467:Phospholipases A2; D012307:Risk Factors; D014657:Vasculitis / Q000188:drug therapy / Q000453:epidemiology / Q000378:metabolism
D004791:Enzyme Inhibitors; D010741:Phospholipases A; D054467:Phospholipases A2; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase