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

Wilensky, Robert L., Shi, Yi, Mohler, Emile R., Hamamdzic, Damir, Burget, Mark E., Li, Jun, Postle, Anthony, Fenning, Robert S., Bollinger, James G., Hoffman, Bryan E., Pelchovitz, Daniel J., Yang, Jisheng, Mirabile, Rosanna C., Webb, Christine L., Zhang, LeFeng, Zhang, Ping, Gelb, Michael H., Walker, Max C., Zalewski, Andrew and Macphee, Colin H. (2008) Inhibition of lipoprotein-associated phospholipase A2 reduces complex coronary atherosclerotic plaque development Nature Medicine, 14, (10), pp. 1059-1066. (doi:10.1038/nm.1870). (PMID:18806801).

Record type: Article

Abstract

Increased lipoprotein-associated phospholipase A2 (Lp-PLA2) activity is associated with increased risk of cardiac events, but it is not known whether Lp-PLA2 is a causative agent. Here we show that selective inhibition of Lp-PLA2 with darapladib reduced development of advanced coronary atherosclerosis in diabetic and hypercholesterolemic swine. Darapladib markedly inhibited plasma and lesion Lp-PLA2 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-PLA2 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

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More information

e-pub ahead of print date: 21 September 2008
Published date: October 2008
Organisations: Infection Inflammation & Immunity

Identifiers

Local EPrints ID: 72649
URI: http://eprints.soton.ac.uk/id/eprint/72649
ISSN: 1078-8956
PURE UUID: b7adc411-5bdb-493e-bcce-e11cdf515f34
ORCID for Anthony Postle: ORCID iD orcid.org/0000-0001-7361-0756

Catalogue record

Date deposited: 19 Feb 2010
Last modified: 18 Jul 2017 23:53

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Contributors

Author: Robert L. Wilensky
Author: Yi Shi
Author: Emile R. Mohler
Author: Damir Hamamdzic
Author: Mark E. Burget
Author: Jun Li
Author: Anthony Postle ORCID iD
Author: Robert S. Fenning
Author: James G. Bollinger
Author: Bryan E. Hoffman
Author: Daniel J. Pelchovitz
Author: Jisheng Yang
Author: Rosanna C. Mirabile
Author: Christine L. Webb
Author: LeFeng Zhang
Author: Ping Zhang
Author: Michael H. Gelb
Author: Max C. Walker
Author: Andrew Zalewski
Author: Colin H. Macphee

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