Recent developments with lipoprotein-associated phospholipase A2 inhibitors.
Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) is a calcium-independent phospholipase A(2) enzyme secreted by leukocytes and associated with circulating low-density lipoprotein and macrophages in atherosclerotic plaques. Until recently, the biological role of Lp-PLA(2) in atherosclerosis was controversial, but now the preponderance of evidence demonstrates a proatherogenic role of this enzyme. Lp-PLA(2) generates two proinflammatory mediators, lysophosphatidylcholine and oxidized nonesterified fatty acids, which play a major role in the development of atherosclerotic lesions and formation of a necrotic core, leading to more vulnerable plaques. These findings have opened the door to a potential novel therapeutic target, selective inhibition of Lp-LPA(2). Recently, both animal models and human studies have shown that selective inhibition of Lp-PLA(2) reduces plasma Lp-PLA(2) activity, plaque area, and necrotic core area. This article reviews the most recent developments with Lp-PLA(2) inhibitors.
Chauffe
Ryan J
RJ
Pennsylvania Hospital, 1 Pine West, 800 Spruce Street, Philadelphia, PA 19107, USA. chauffer@uphs.upenn.edu
Wilensky
Robert L
RL
Mohler
Emile R
ER
D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase / Q000037:antagonists & inhibitors* / Q000097:blood; D050197:Atherosclerosis / Q000150:complications / Q000188:drug therapy* / Q000201:enzymology; D015507:Drugs, Investigational; D006801:Humans; D007962:Leukocytes / Q000201:enzymology; D008077:Lipoproteins, LDL / Q000097:blood / Q000187:drug effects; D008264:Macrophages / Q000201:enzymology; D009203:Myocardial Infarction / Q000201:enzymology / Q000209:etiology / Q000517:prevention & control*; D012307:Risk Factors; D016896:Treatment Outcome
D015507:Drugs, Investigational; D008077:Lipoproteins, LDL; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase