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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:600.)
© 2007 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Group V Secretory Phospholipase A₂ Promotes Atherosclerosis

Evidence From Genetically Altered Mice

Meredith A. Bostrom; Boris B. Boyanovsky; Craig T. Jordan; Marilyn P. Wadsworth; Douglas J. Taatjes; Frederick C. de Beer; Nancy R. Webb

From the Graduate Center for Nutritional Sciences (M.A.B., F.C.d.B., N.R.W.) and the Department of Internal Medicine (B.B.B., F.C.d.B., N.R.W.), University of Kentucky, Lexington; Veterans Affairs Medical Center (F.C.d.B.), Lexington, Ky; James P. Wilmot Cancer Center (C.T.J.), University of Rochester Medical Center, NY; and the Department of Pathology (M.P.W., D.J.T.), College of Medicine, University of Vermont, Burlington.

Correspondence to Nancy R. Webb, PhD, 900 South Limestone Street Rm 535, University of Kentucky, Lexington, KY 40536-0200. E-mail nrwebb1{at}uky.edu

Objective— Group V secretory phospholipase A₂ (GV sPLA₂) has been detected in both human and mouse atherosclerotic lesions. This enzyme has potent hydrolytic activity towards phosphatidylcholine-containing substrates, including lipoprotein particles. Numerous studies in vitro indicate that hydrolysis of high density lipoproteins (HDL) and low density lipoproteins (LDL) by GV sPLA₂ leads to the formation of atherogenic particles and potentially proinflammatory lipid mediators. However, there is no direct evidence that this enzyme promotes atherogenic processes in vivo.

Methods and Results— We performed gain-of-function and loss-of-function studies to investigate the role of GV sPLA₂ in atherogenesis in LDL receptor–deficient mice. Compared with control mice, animals overexpressing GV sPLA₂ by retrovirus-mediated gene transfer had a 2.7 fold increase in lesion area in the ascending region of the aortic root. Increased atherosclerosis was associated with an increase in lesional collagen deposition in the same region. Mice deficient in bone marrow–derived GV sPLA₂ had a 36% reduction in atherosclerosis in the aortic arch/thoracic aorta.

Conclusions— Our data in mouse models provide the first in vivo evidence that GV sPLA₂ contributes to atherosclerotic processes, and draw attention to this enzyme as an attractive target for the treatment of atherosclerotic disease.

GV sPLA₂ has been implicated in atherosclerosis in vitro. We demonstrate in mice that overexpression of GV sPLA₂ in bone marrow cells results in increased atherosclerosis, whereas deficiency results in a reduction of atherosclerosis. We provide the first in vivo evidence that GV sPLA₂ promotes atherosclerosis.

Key Words: Group V secretory phospholipase A₂ • atherosclerosis • retrovirus-mediated gene transfer • bone marrow transplantation

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