This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 29/1/19    most recent ATVBAHA.108.176644v1 Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Manning-Tobin, J. J. Articles by Freeman, M. W. Search for Related Content PubMed PubMed Citation Articles by Manning-Tobin, J. J. Articles by Freeman, M. W. Related Collections Cell signalling/signal transduction Genetically altered mice Lipid and lipoprotein metabolism Mechanism of atherosclerosis/growth factors

(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

This article has been cited by other articles:

				I. Grosheva, A. S. Haka, C. Qin, L. M. Pierini, and F. R. Maxfield Aggregated LDL in Contact With Macrophages Induces Local Increases in Free Cholesterol Levels That Regulate Local Actin Polymerization Arterioscler Thromb Vasc Biol, October 1, 2009; 29(10): 1615 - 1621. [Abstract] [Full Text] [PDF]

				D. J. Kennedy, S. D. Kuchibhotla, E. Guy, Y. M. Park, G. Nimako, D. Vanegas, R. E. Morton, and M. Febbraio Dietary Cholesterol Plays a Role in CD36-Mediated Atherogenesis in LDLR-Knockout Mice Arterioscler Thromb Vasc Biol, October 1, 2009; 29(10): 1481 - 1487. [Abstract] [Full Text] [PDF]

				G. Xu, T. Watanabe, Y. Iso, S. Koba, T. Sakai, M. Nagashima, S. Arita, S. Hongo, H. Ota, Y. Kobayashi, et al. Preventive Effects of Heregulin-{beta}1 on Macrophage Foam Cell Formation and Atherosclerosis Circ. Res., August 28, 2009; 105(5): 500 - 510. [Abstract] [Full Text] [PDF]

				Y. Etzion, A. Hackett, B. M. Proctor, J. Ren, B. Nolan, T. Ellenberger, and A. J. Muslin An Unbiased Chemical Biology Screen Identifies Agents That Modulate Uptake of Oxidized LDL by Macrophages Circ. Res., July 17, 2009; 105(2): 148 - 157. [Abstract] [Full Text] [PDF]

				C. Erridge CD36: promotion from scavenger receptor to mediator of migration? Cardiovasc Res, July 1, 2009; 83(1): 5 - 6. [Full Text] [PDF]

				R. L. Silverstein and M. Febbraio CD36, a Scavenger Receptor Involved in Immunity, Metabolism, Angiogenesis, and Behavior Sci. Signal., May 26, 2009; 2(72): re3 - re3. [Abstract] [Full Text] [PDF]