title: Requirement of JNK2 for scavenger receptor A-mediated foam cell formation in atherogenesis.
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.
authors.affiliation: Cardiovascular Research, Institute of Physiology, and Division of Cardiology, University Hospital Zurich, CH-8057 Zurich, Switzerland. romeo.ricci@cell.biol.ethz.ca
authors.forename: Romeo
authors.initials: R
authors.lastname: Ricci
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Sumara
authors.forename: Izabela
authors.initials: I
authors.lastname: Sumara
authors.forename: Izabela
authors.initials: I
authors.lastname: Rozenberg
authors.forename: Michael
authors.initials: M
authors.lastname: Kurrer
authors.forename: Alexander
authors.initials: A
authors.lastname: Akhmedov
authors.forename: Martin
authors.initials: M
authors.lastname: Hersberger
authors.forename: Urs
authors.initials: U
authors.lastname: Eriksson
authors.forename: Franz R
authors.initials: FR
authors.lastname: Eberli
authors.forename: Burkhard
authors.initials: B
authors.lastname: Becher
authors.forename: Jan
authors.initials: J
authors.lastname: Borén
authors.forename: Mian
authors.initials: M
authors.lastname: Chen
authors.forename: Myron I
authors.initials: MI
authors.lastname: Cybulsky
authors.forename: Kathryn J
authors.initials: KJ
authors.lastname: Moore
authors.forename: Mason W
authors.initials: MW
authors.lastname: Freeman
authors.forename: Erwin F
authors.initials: EF
authors.lastname: Wagner
authors.forename: Christian M
authors.initials: CM
authors.lastname: Matter
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Lüscher
mesh_terms: D000818:Animals; D001011:Aorta / Q000737:chemistry / Q000473:pathology; D001057:Apolipoproteins E / Q000235:genetics; D001161:Arteriosclerosis / Q000378:metabolism* / Q000473:pathology; D016026:Bone Marrow Transplantation; D018955:CD36 Antigens / Q000378:metabolism; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism; D002791:Cholesterol, Dietary / Q000008:administration & dosage; D004036:Diet, Atherogenic; D042783:Endothelial Cells / Q000502:physiology; D005487:Foam Cells / Q000378:metabolism*; D008077:Lipoproteins, LDL / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism*; D017737:Macrophages, Peritoneal / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D048055:Mitogen-Activated Protein Kinase 8 / Q000378:metabolism; D048056:Mitogen-Activated Protein Kinase 9 / Q000235:genetics / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D032389:Myocytes, Smooth Muscle / Q000502:physiology; D010766:Phosphorylation; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*; D051116:Receptors, Scavenger; D051117:Scavenger Receptors, Class A; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D001057:Apolipoproteins E; D018955:CD36 Antigens; D002791:Cholesterol, Dietary; D008077:Lipoproteins, LDL; C495140:Msr1 protein, mouse; D011971:Receptors, Immunologic; D051116:Receptors, Scavenger; D051117:Scavenger Receptors, Class A; C032629:acetyl-LDL; C099252:oxidized low density lipoprotein; D002784:Cholesterol; D048056:Mitogen-Activated Protein Kinase 9; D048055:Mitogen-Activated Protein Kinase 8