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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2003;23:263.)
© 2003 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Macrophage-Expressed Group IIA Secretory Phospholipase A₂ Increases Atherosclerotic Lesion Formation in LDL Receptor–Deficient Mice

Nancy R. Webb; Meredith A. Bostrom; Stephen J. Szilvassy; Deneys R. van der Westhuyzen; Alan Daugherty; Frederick C. de Beer

From the Department of Internal Medicine, the Gill Heart Institute (A.D.), and the Blood and Marrow Transplant Program (S.J.S.), University of Kentucky Medical Center, Lexington, Ky.

Correspondence to N.R. Webb, PhD, Department of Internal Medicine, University of Kentucky Medical Center MN520, 800 Rose St, Lexington, KY 40536-0084. E-mail nrwebb1{at}uky.edu

Objective— Transgenic mice expressing human group IIA secretory phospholipase A₂ (group IIA sPLA₂) spontaneously develop atherosclerotic lesions. The mechanism for this proatherogenic effect is likely multifactorial, because HDL-cholesterol is significantly lower and LDL/VLDL cholesterol is slightly higher in transgenic mice compared with nontransgenic littermates. In the present study, we show for the first time that elicited peritoneal macrophages from transgenic mice express human group IIA sPLA₂. This study tested whether macrophage-expressed sPLA₂ contributes to atherogenesis.

Methods and Results— Bone marrow cells from either sPLA₂ transgenic mice or control C57BL/6 mice were transplanted into LDL receptor–deficient mice. After hematopoietic engraftment, animals were fed a diet enriched with saturated fat and cholesterol for 12 weeks. Despite a lack of effect on serum lipoprotein concentrations, the presence of bone marrow–derived cells expressing human group IIA sPLA₂ resulted in a significant increase in the extent of atherosclerosis in the aortic arch (12.8±1.4% versus 7.4±0.9%; P<0.005) and aortic sinus (0.3±0.03 mm² versus 0.2±0.04 mm²; P<0.05).

Conclusions— Group IIA sPLA₂ can contribute to atherosclerotic lesion development through a mechanism that is independent of systemic lipoprotein metabolism.

Key Words: atherosclerosis • bone marrow transplant • transgenic mice • group IIA secretory phospholipase A₂ • macrophages

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