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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Acknowledgements
The superb animal husbandry of H. Profka is gratefully acknowledged. We greatly appreciate the input by M. Hurle into the design and confirmation of the Taqman probes and the advice and support related to immunofluorescence procedures of P. Crino. These studies were supported by funding from GlaxoSmithKline through an industry-academic alliance via the Alternative Drug Discovery Initiative with the University of Pennsylvania School of Medicine. M.H.G. is funded by US National Institutes of Health grant R37HL036235.
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R.L.W., Y.S., E.R.M., III, M.C.W., A.Z. and C.H.M. conceived and designed the project and analyzed all data. R.L.W. and C.H.M. wrote the manuscript. Y.S., L.Z. and P.Z. performed studies on vascular inflammation. D.H., R.S.F., D.J.P., J.Y. and R.C.M. performed the histological and immunohistochemical analyses. M.E.B. performed statistical analysis. J.L. and B.E.H. performed the real-time PCR. A.P. performed the mass spectrometry. J.G.B. and M.H.G. determined selectivity of darapladib. C.L.W. carried out the analysis of Lp-PLA2 activity.
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R.L.W., Y.S., E.R.M., III and A.P. are recipients of research grants from GlaxoSmithKline. M.E.B., B.E.H., R.C.M.,C.L.W., M.C.W., A.Z. and C.H.M. are employees of GlaxoSmithKline, the manufacturer of darapladib.
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Wilensky, R., Shi, Y., Mohler, E. et al. Inhibition of lipoprotein-associated phospholipase A2 reduces complex coronary atherosclerotic plaque development. Nat Med 14, 1059–1066 (2008). https://doi.org/10.1038/nm.1870
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DOI: https://doi.org/10.1038/nm.1870
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