Inhibition of lipoprotein-associated phospholipase A2 reduces complex coronary atherosclerotic plaque development.
Increased lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) activity is associated with increased risk of cardiac events, but it is not known whether Lp-PLA(2) is a causative agent. Here we show that selective inhibition of Lp-PLA(2) with darapladib reduced development of advanced coronary atherosclerosis in diabetic and hypercholesterolemic swine. Darapladib markedly inhibited plasma and lesion Lp-PLA(2) activity and reduced lesion lysophosphatidylcholine content. Analysis of coronary gene expression showed that darapladib exerted a general anti-inflammatory action, substantially reducing the expression of 24 genes associated with macrophage and T lymphocyte functioning. Darapladib treatment resulted in a considerable decrease in plaque area and, notably, a markedly reduced necrotic core area and reduced medial destruction, resulting in fewer lesions with an unstable phenotype. These data show that selective inhibition of Lp-PLA(2) inhibits progression to advanced coronary atherosclerotic lesions and confirms a crucial role of vascular inflammation independent from hypercholesterolemia in the development of lesions implicated in the pathogenesis of myocardial infarction and stroke.
Wilensky
Robert L
RL
Hospital of the University of Pennsylvania, 3400 Spruce Street, 9 Gates, Philadelphia, Pennsylvania 19104, USA. robert.wilensky@uphs.upenn.edu
Shi
Yi
Y
Mohler
Emile R
ER
Hamamdzic
Damir
D
Burgert
Mark E
ME
Li
Jun
J
Postle
Anthony
A
Fenning
Robert S
RS
Bollinger
James G
JG
Hoffman
Bryan E
BE
Pelchovitz
Daniel J
DJ
Yang
Jisheng
J
Mirabile
Rosanna C
RC
Webb
Christine L
CL
Zhang
LeFeng
L
Zhang
Ping
P
Gelb
Michael H
MH
Walker
Max C
MC
Zalewski
Andrew
A
Macphee
Colin H
CH
D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase / Q000037:antagonists & inhibitors* / Q000097:blood / Q000502:physiology; D000818:Animals; D001547:Benzaldehydes / Q000494:pharmacology* / Q000627:therapeutic use; D003324:Coronary Artery Disease / Q000473:pathology / Q000517:prevention & control*; D003331:Coronary Vessels / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D008297:Male; D010091:Oximes / Q000494:pharmacology* / Q000627:therapeutic use; D010713:Phosphatidylcholines / Q000097:blood; D013552:Swine; D001713:Biphenyl Compounds; D004048:Diethylamines; D011744:Pyrimidinones; D013440:Sulfides
D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; D001547:Benzaldehydes; D004791:Enzyme Inhibitors; D010091:Oximes; D010713:Phosphatidylcholines; C529040:darapladib; D001713:Biphenyl Compounds; D004048:Diethylamines; D011744:Pyrimidinones; D013440:Sulfides