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.

Nyckelord

Animals

Antigens

CD36/metabolism

Aorta/chemistry/pathology

Apolipoproteins E/genetics

Arteriosclerosis/*metabolism/pathology

Bone Marrow Transplantation

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

Publikations- och innehållstyp

ref (ämneskategori)

art (ämneskategori)