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

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
DOI: 10.1126/science.1101909 Publication Date: 2004-11-26T14:42:48Z
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.
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