Requirement of JNK2 for scavenger receptor A-mediated foam cell formation in atherogenesis.
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.
Ricci
Romeo
R
Cardiovascular Research, Institute of Physiology, and Division of Cardiology, University Hospital Zurich, CH-8057 Zurich, Switzerland. romeo.ricci@cell.biol.ethz.ca
Sumara
Grzegorz
G
Sumara
Izabela
I
Rozenberg
Izabela
I
Kurrer
Michael
M
Akhmedov
Alexander
A
Hersberger
Martin
M
Eriksson
Urs
U
Eberli
Franz R
FR
Becher
Burkhard
B
Borén
Jan
J
Chen
Mian
M
Cybulsky
Myron I
MI
Moore
Kathryn J
KJ
Freeman
Mason W
MW
Wagner
Erwin F
EF
Matter
Christian M
CM
Lüscher
Thomas F
TF
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
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