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

• DOI: 10.1126/science.1101909
• Publication Date: 2004-11-26T14:42:48Z
• Authors: Romeo Ricci; Grzegorz Sumara; Izabela Sumara; Izabela Rozenberg; Michael Kurrer; Alexander Akhmedov; Martin Hersberger; Urs Eriksson; Franz R. Eberli; Burkhard Becher; Jan Borén; Mian Chen; Myron I. Cybulsky; Kathryn J. Moore; Mason W. Freeman; Erwin F. Wagner; Christian M. Matter; Thomas F. Lüscher
• Keywords: CD36 Antigens; Mice, Knockout; 0303 health sciences; Arteriosclerosis; Macrophages; Endothelial Cells; [SDV] Life Sciences [q-bio]; Cholesterol, Dietary; Lipoproteins, LDL; Mice, Inbred C57BL; Mice; 03 medical and health sciences; Apolipoproteins E; Cholesterol; Macrophages, Peritoneal; Animals; Diet, Atherogenic; Mitogen-Activated Protein Kinase 9; Mitogen-Activated Protein Kinase 8; Aorta; Cells, Cultured; Bone Marrow Transplantation; Foam Cells

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.