Lipoprotein-associated phospholipase A2: a potential therapeutic target for atherosclerosis.
Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) is an enzyme that is produced by inflammatory cells, is bound to circulating LDL, and is involved in hydrolyzing polar phospholipids, including those found in oxidized low-density lipoproteins. To date, the biological role of Lp-PLA(2) in atherogenesis has been controversial, with initial reports purporting an atheroprotective effect attributable to the degradation of platelet activating factor and similar molecules. However, more recent studies suggest a proatherogenic role for this enzyme, which is attributed to Lp-PLA(2)-mediated hydrolysis of oxidatively modified low-density lipoproteins that results in the accumulation of proinflammatory products. The liberation of lysophosphatidylcholine and oxidized nonesterified fatty acids from oxidized phospholipids by the action of Lp-PLA(2) results in diverse inflammatory effects on various cell types involved in atherogenesis. This concept is further supported by a number of recently published epidemiology studies suggesting that plasma levels of the enzyme predict future cardiovascular events independent of conventional risk factors. The development of selective inhibitors of Lp-PLA(2) that inhibit enzyme activity in the circulation as well as within human atherosclerotic lesions opens the possibility of therapeutic manipulation of vascular inflammatory processes to reduce residual cardiovascular events in high risk individuals who continue to suffer fatal and nonfatal events despite the current standard of care.
Zalewski
A
A
GlaxoSmithKline, Medicine Development Centre, King of Prussia, PA 19406, USA. andrew.2.zalewski@gsk.com
Macphee
C
C
Nelson
J J
JJ
D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; D050197:Atherosclerosis / Q000188:drug therapy* / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D010741:Phospholipases A / Q000037:antagonists & inhibitors* / Q000378:metabolism; D054467:Phospholipases A2; D012307:Risk Factors
D004791:Enzyme Inhibitors; D010741:Phospholipases A; D054467:Phospholipases A2; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase