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Science 306 (5701): 1558-1561

Copyright © 2004 by the American Association for the Advancement of Science

Requirement of JNK2 for Scavenger Receptor A-Mediated Foam Cell Formation in Atherogenesis

Romeo Ricci,1,2*{dagger} Grzegorz Sumara,1,2{dagger} Izabela Sumara,3 Izabela Rozenberg,1 Michael Kurrer,4 Alexander Akhmedov,1 Martin Hersberger,5 Urs Eriksson,7 Franz R. Eberli,1 Burkhard Becher,6 Jan Borén,8 Mian Chen,9 Myron I. Cybulsky,9 Kathryn J. Moore,10 Mason W. Freeman,10 Erwin F. Wagner,11 Christian M. Matter,1{ddagger} Thomas F. Lüscher1{ddagger}

Abstract: In vitro studies suggest a role for c-Jun N-terminal kinases (JNKs) in proatherogenic cellular processes. We show that atherosclerosis-prone ApoE–/– mice simultaneously lacking JNK2 (ApoE–/– JNK2–/– mice), but not ApoE–/– JNK1–/– mice, developed less atherosclerosis than do ApoE–/– mice. Pharmacological inhibition of JNK activity efficiently reduced plaque formation. Macrophages lacking JNK2 displayed suppressed foam cell formation caused by defective uptake and degradation of modified lipoproteins and showed increased amounts of the modified lipoprotein-binding and -internalizing scavenger receptor A (SR-A), whose phosphorylation was markedly decreased. Macrophage-restricted deletion of JNK2 was sufficient to decrease atherogenesis. Thus, JNK2-dependent phosphorylation of SR-A promotes uptake of lipids in macrophages, thereby regulating foam cell formation, a critical step in atherogenesis.

1 Cardiovascular Research, Institute of Physiology, and Division of Cardiology, University Hospital Zurich, CH-8057 Zurich, Switzerland.
2 Institute of Cell Biology, Eidgenössische Technische Hochschule, Hönggerberg, CH-8093 Zurich, Switzerland.
3 Institute of Biochemistry, Eidgenössische Technische Hochschule, Hönggerberg, CH-8093 Zurich, Switzerland.
4 Department of Pathology, University Hospital Zurich, CH-8091 Zurich, Switzerland.
5 Institute of Clinical Chemistry, University Hospital Zurich, CH-8091 Zurich, Switzerland.
6 Department of Neurology/Neuroimmunology Unit, University Hospital Zurich, CH-8091 Zurich, Switzerland.
7 Experimental Critical Care Medicine, Department of Research and Medicine A, Basel University Hospital, CH-4031 Basel, Switzerland.
8 Wallenberg Laboratory for Cardiovascular Research, Goteborg University, Goteborg S-4345, Sweden.
9 Toronto General Research Institute and Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
10 Lipid Metabolism Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
11 Institute of Molecular Pathology, A-1030 Vienna, Austria.

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{dagger} These authors contributed equally to this work.

{ddagger} These authors contributed equally to this work.

* To whom correspondence should be addressed. E-mail: romeo.ricci{at}cell.biol.ethz.ch

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