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: 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
• Journal: Science (New York, N.Y.) (Science) Vol. 306 Issue 5701 Pg. 1558-61 (Nov 26 2004) ISSN: 1095-9203 [Electronic] United States
• PMID: 15567863 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Apolipoproteins E
• CD36 Antigens
• Cholesterol, Dietary
• Lipoproteins, LDL
• Msr1 protein, mouse
• Receptors, Immunologic
• Receptors, Scavenger
• Scavenger Receptors, Class A
• acetyl-LDL
• oxidized low density lipoprotein
• Cholesterol
• Mitogen-Activated Protein Kinase 9
• Mitogen-Activated Protein Kinase 8

Topics

• Animals
• Aorta (chemistry, pathology)
• Apolipoproteins E (genetics)
• Arteriosclerosis (metabolism, pathology)
• Bone Marrow Transplantation
• CD36 Antigens (metabolism)
• Cells, Cultured
• Cholesterol (metabolism)
• Cholesterol, Dietary (administration & dosage)
• Diet, Atherogenic
• Endothelial Cells (physiology)
• Foam Cells (metabolism)
• Lipoproteins, LDL (metabolism)
• Macrophages (metabolism)
• Macrophages, Peritoneal (physiology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Mitogen-Activated Protein Kinase 8 (metabolism)
• Mitogen-Activated Protein Kinase 9 (genetics, metabolism)
• Muscle, Smooth, Vascular (cytology)
• Myocytes, Smooth Muscle (physiology)
• Phosphorylation
• Receptors, Immunologic (genetics, metabolism)
• Receptors, Scavenger
• Scavenger Receptors, Class A
• T-Lymphocytes (immunology)