Inhibition of lipoprotein-associated phospholipase A2 reduces complex coronary atherosclerotic plaque development

被引：308

作者：

Wilensky, Robert L. ^{[1
]}

Shi, Yi ^{[2
]}

Mohler, Emile R., III ^{[1
]}

Hamamdzic, Damir ^{[1
]}

Burgert, Mark E.

Li, Jun ^{[3
]}

Postle, Anthony ^{[4
]}

Fenning, Robert S. ^{[1
]}

Bollinger, James G. ^{[5
,6
]}

Hoffman, Bryan E. ^{[3
]}

Pelchovitz, Daniel J. ^{[1
]}

Yang, Jisheng ^{[1
]}

Mirabile, Rosanna C. ^{[3
]}

Webb, Christine L. ^{[3
]}

Zhang, LeFeng ^{[2
]}

Zhang, Ping ^{[2
]}

Gelb, Michael H. ^{[5
,6
]}

Walker, Max C. ^{[3
]}

Zalewski, Andrew ^{[2
,3
]}

Macphee, Colin H. ^{[3
]}

机构：

[1] Hosp Univ Penn, Philadelphia, PA 19104 USA

[2] Thomas Jefferson Univ, Philadelphia, PA 19107 USA

[3] GlaxoSmithKline Inc, King Of Prussia, PA 19406 USA

[4] Southampton Gen Hosp, Div Infect Inflammat & Repair, Southampton SO16 6YD, Hants, England

[5] Univ Washington, Dept Chem, Seattle, WA 98195 USA

[6] Univ Washington, Dept Biochem, Seattle, WA 98195 USA

来源：

NATURE MEDICINE | 2008年 / 14卷 / 10期

基金：

美国国家卫生研究院;

关键词：

D O I：

10.1038/nm.1870

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：1059 / 1066

页数：8

共 46 条

[1] Impaired clearance of apoptotic cells promotes synergy between atherogenesis and autoimmune disease [J].