Lipoprotein-associated phospholipase A(2) and atherosclerosis.
OBJECTIVE
There is substantial data from over 50 000 patients that increased lipoprotein-associated phospholipase A2 (Lp-PLA2) mass or activity is associated with an increased risk of cardiac death, myocardial infarction, acute coronary syndromes and ischemic stroke. However, only recently have data emerged demonstrating a role of Lp-PLA2 in development of advanced coronary artery disease. Indeed, Lp-PLA2 may be an important link between lipid homeostasis and the vascular inflammatory response.


RESULTS
Lp-PLA2, also known as platelet-activating factor acetylhydrolase, rapidly cleaves oxidized phosphatidylcholine molecules produced during the oxidation of LDL and atherogenic lipoprotein Lp(a), generating the soluble proinflammatory and proapoptotic lipid mediators, lyso-phosphatidylcholine and oxidized nonesterified fatty acids. These proinflammatory lipids play an important role in the development of atherosclerotic necrotic cores, the substrate for acute unstable coronary disease by recruiting and activating leukocytes/macrophages, inducing apoptosis and impairing the subsequent removal of dead cells. Selective inhibition of Lp-PLA2 reduces development of necrotic cores and may result in stabilization of atherosclerotic plaques.


CONCLUSIONS
Recent data have shown that immune pathways play a major role in the development and progression of high-risk atherosclerosis, which leads to ischemic sudden death, myocardial infarction, acute coronary syndromes and ischemic strokes. Persistent and sustained macrophage apoptosis appears to play a major role in the resulting local inflammatory response in part by effects elicited by Lp-PLA2. Selective inhibition of Lp-PLA2 has been postulated to reduce necrotic core progression and the clinical sequelae of advanced, unstable atherosclerosis.
Wilensky
Robert L
RL
Cardiovascular Division, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. robert.wilensky@uphs.upenn.edu
Macphee
Colin H
CH
D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D050197:Atherosclerosis / Q000188:drug therapy / Q000201:enzymology* / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D010084:Oxidation-Reduction; D010743:Phospholipids / Q000378:metabolism
D015415:Biomarkers; D004791:Enzyme Inhibitors; D010743:Phospholipids; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase