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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2009;29:19.)
© 2009 American Heart Association, Inc.

Integrative Physiology/Experimental Medicine

Loss of SR-A and CD36 Activity Reduces Atherosclerotic Lesion Complexity Without Abrogating Foam Cell Formation in Hyperlipidemic Mice

Jennifer J. Manning-Tobin; Kathryn J. Moore; Tracie A. Seimon; Susan A. Bell; Maia Sharuk; Jacqueline I. Alvarez-Leite; Menno P.J. de Winther; Ira Tabas; Mason W. Freeman

From the Lipid Metabolism Unit (J.J.M.-T., K.J.M., S.A.B., M.S., J.I.A.-L., M.W.F.) and the Center for Computational & Integrative Biology (M.W.F.), Massachusetts General Hospital, Harvard Medical School, Boston; the Department of Medicine (T.A.S., I.T.) and the Departments of Pathology & Cell Biology and Physiology & Cellular Biophysics (I.T.), Columbia University, New York; the Federal University of Minas Gerais (J.I.A.-L.), Belo Horizonte, Brazil; and the Department of Molecular Genetics (M.P.J.d.W.), Cardiovascular Research Institute Maastricht, Maastricht University, The Netherlands.

Correspondence to Mason W. Freeman, Harvard Medical School, Massachusetts General Hospital, Boston, MA 02114. E-mail freeman{at}molbio.mgh.harvard.edu

Objective— The scavenger receptors SR-A and CD36 have been implicated in macrophage foam cell formation during atherogenesis and in the regulation of inflammatory signaling pathways, including those leading to lesional macrophage apoptosis and plaque necrosis. To test the impact of deleting these receptors, we generated Apoe^–/– mice lacking both SR-A and CD36 and fed them a Western diet for 12 weeks.

Methods and Results— We analyzed atheroma in mice, assessing lesion size, foam cell formation, inflammatory gene expression, apoptosis, and necrotic core formation. Aortic root atherosclerosis in Apoe^–/–Cd36^–/–Msr1^–/– mice, as assessed by morphometry, electron microscopy, and immunohistochemistry, showed no decrease in lesion area or in vivo foam cell formation when compared to Apoe^–/– mice. However, Apoe^–/–Cd36^–/–Msr1^–/– lesions showed reduced expression of inflammatory genes and morphological analysis revealed a 30% decrease in macrophage apoptosis and a striking 50% decrease in plaque necrosis in aortic root lesions of these mice.

Conclusions— Although targeted deletion of SR-A and CD36 does not abrogate macrophage foam cell formation or substantially reduce atherosclerotic lesion area in Apoe^–/– mice, loss of these pathways does reduce progression to more advanced necrotic lesions. These data suggest that targeted inhibition of these pathways in vivo may reduce lesional inflammation and promote plaque stability.

Key Words: scavenger receptor • atherosclerosis • apoptosis • necrosis • inflammation

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