Babaev, V. R.Yeung, M.Erbay, E.Ding, L.Zhang, Y.May, J. M.Fazio, S.Hotamisligil, G. S.Linton, M. F.2018-04-122018-04-1220161079-5642http://hdl.handle.net/11693/37164Objective - The c-Jun NH 2 -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.EnglishApoptosisAtherosclerosisEndoplasmic reticulum stressMacrophagesMAP kinase signaling systemAnisomycinAnthra[1,9 cd]pyrazol 6(2h) oneInsulinJNKI1Low density lipoprotein receptorMitogen activated protein kinase p38Phosphatidylinositol 3,4,5 trisphosphate 3 phosphataseProtein kinase BStress activated protein kinase 1Unclassified drugBad protein, mouseLow density lipoprotein receptorMitogen activated protein kinase 9Protein BADProtein kinase BProtein kinase inhibitorPten protein, mouseStress activated protein kinase 1AlleleAnimal cellAnimal experimentAnimal modelApoptosisArticleAtherosclerosisCholesterol dietControlled studyEndoplasmic reticulum stressEnzyme activityEnzyme deficiencyEnzyme inhibitionGene repressionHematopoietic cellMacrophageMouseNonhumanPriority journalSignal transductionAnimalAntagonists and inhibitorsAortaAortic diseaseApoptosisAtherosclerosisAtherosclerotic plaqueBone marrow cellBone marrow transplantationC57BL mouseCell cultureCell survivalDeficiencyDisease modelDrug effectsEnzymologyGenetic predispositionGeneticsHypercholesterolemiaKnockout mouseLipid dietMetabolismPathologyPhenotypeAnimalsAortaAortic DiseasesApoptosisAtherosclerosisBcl-Associated Death ProteinBone Marrow CellsBone Marrow TransplantationCell SurvivalCells, CulturedDiet, High-FatDisease Models, AnimalEndoplasmic Reticulum StressGenetic Predisposition to DiseaseHypercholesterolemiaMacrophagesInbred C57BLKnockoutMitogen-Activated Protein Kinase 8Mitogen-Activated Protein Kinase 9PhenotypeAtheroscleroticProtein Kinase InhibitorsProto-Oncogene Proteins c-aktPTEN PhosphohydrolaseReceptorsSignal TransductionArticle10.1161/ATVBAHA.116.307580