Jnk1 Deficiency in Hematopoietic Cells Suppresses Macrophage Apoptosis and Increases Atherosclerosis in Low-Density Lipoprotein Receptor Null Mice.

Babaev VR, Yeung M, Erbay E, Ding L, Zhang Y, May JM, Fazio S, Hotamisligil GS, Linton MF
Arterioscler Thromb Vasc Biol. 2016 36 (6): 1122-31

PMID: 27102962 · PMCID: PMC4882236 · DOI:10.1161/ATVBAHA.116.307580

OBJECTIVE - The c-Jun NH2-terminal kinases (JNK) are regulated by a wide variety of cellular stresses and have been implicated in apoptotic signaling. Macrophages express 2 JNK isoforms, JNK1 and JNK2, which may have different effects on cell survival and atherosclerosis.

APPROACH AND RESULTS - To dissect the effect of macrophage JNK1 and JNK2 on early atherosclerosis, Ldlr(-/-) mice were reconstituted with wild-type, Jnk1(-/-), and Jnk2(-/-) hematopoietic cells and fed a high cholesterol diet. Jnk1(-/-)→Ldlr(-/-) mice have larger atherosclerotic lesions with more macrophages and fewer apoptotic cells than mice transplanted with wild-type or Jnk2(-/-) cells. Moreover, genetic ablation of JNK to a single allele (Jnk1(+/-)/Jnk2(-/-) or Jnk1(-/-)/Jnk2(+/-)) in marrow of Ldlr(-/-) recipients further increased atherosclerosis compared with Jnk1(-/-)→Ldlr(-/-) and wild-type→Ldlr(-/-) mice. In mouse macrophages, anisomycin-mediated JNK signaling antagonized Akt activity, and loss of Jnk1 gene obliterated this effect. Similarly, pharmacological inhibition of JNK1, but not JNK2, markedly reduced the antagonizing effect of JNK on Akt activity. Prolonged JNK signaling in the setting of endoplasmic reticulum stress gradually extinguished Akt and Bad activity in wild-type cells with markedly less effects in Jnk1(-/-) macrophages, which were also more resistant to apoptosis. Consequently, anisomycin increased and JNK1 inhibitors suppressed endoplasmic reticulum stress-mediated apoptosis in macrophages. We also found that genetic and pharmacological inhibition of phosphatase and tensin homolog abolished the JNK-mediated effects on Akt activity, indicating that phosphatase and tensin homolog mediates crosstalk between these pathways.

CONCLUSIONS - Loss of Jnk1, but not Jnk2, in macrophages protects them from apoptosis, increasing cell survival, and this accelerates early atherosclerosis.

© 2016 American Heart Association, Inc.

MeSH Terms (27)

Animals Aorta Aortic Diseases Apoptosis Atherosclerosis bcl-Associated Death Protein Bone Marrow Cells Bone Marrow Transplantation Cells, Cultured Cell Survival Diet, High-Fat Disease Models, Animal Endoplasmic Reticulum Stress Genetic Predisposition to Disease Hypercholesterolemia Macrophages Mice, Inbred C57BL Mice, Knockout Mitogen-Activated Protein Kinase 8 Mitogen-Activated Protein Kinase 9 Phenotype Plaque, Atherosclerotic Protein Kinase Inhibitors Proto-Oncogene Proteins c-akt PTEN Phosphohydrolase Receptors, LDL Signal Transduction

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