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      Jnk1 deficiency in hematopoietic cells suppresses macrophage apoptosis and increases atherosclerosis in low-density lipoprotein receptor null mice

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      Author(s)
      Babaev, V. R.
      Yeung, M.
      Erbay, E.
      Ding, L.
      Zhang, Y.
      May, J. M.
      Fazio, S.
      Hotamisligil, G. S.
      Linton, M. F.
      Date
      2016
      Source Title
      Arteriosclerosis, Thrombosis, and Vascular Biology
      Print ISSN
      1079-5642
      Publisher
      Lippincott Williams and Wilkins
      Volume
      36
      Issue
      6
      Pages
      1122 - 1131
      Language
      English
      Type
      Article
      Item Usage Stats
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      84
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      Abstract
      Objective - 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.
      Keywords
      Apoptosis
      Atherosclerosis
      Endoplasmic reticulum stress
      Macrophages
      MAP kinase signaling system
      Anisomycin
      Anthra[1,9 cd]pyrazol 6(2h) one
      Insulin
      JNKI1
      Low density lipoprotein receptor
      Mitogen activated protein kinase p38
      Phosphatidylinositol 3,4,5 trisphosphate 3 phosphatase
      Protein kinase B
      Stress activated protein kinase 1
      Unclassified drug
      Bad protein, mouse
      Low density lipoprotein receptor
      Mitogen activated protein kinase 9
      Protein BAD
      Protein kinase B
      Protein kinase inhibitor
      Pten protein, mouse
      Stress activated protein kinase 1
      Allele
      Animal cell
      Animal experiment
      Animal model
      Apoptosis
      Article
      Atherosclerosis
      Cholesterol diet
      Controlled study
      Endoplasmic reticulum stress
      Enzyme activity
      Enzyme deficiency
      Enzyme inhibition
      Gene repression
      Hematopoietic cell
      Macrophage
      Mouse
      Nonhuman
      Priority journal
      Signal transduction
      Animal
      Antagonists and inhibitors
      Aorta
      Aortic disease
      Apoptosis
      Atherosclerosis
      Atherosclerotic plaque
      Bone marrow cell
      Bone marrow transplantation
      C57BL mouse
      Cell culture
      Cell survival
      Deficiency
      Disease model
      Drug effects
      Enzymology
      Genetic predisposition
      Genetics
      Hypercholesterolemia
      Knockout mouse
      Lipid diet
      Metabolism
      Pathology
      Phenotype
      Animals
      Aorta
      Aortic Diseases
      Apoptosis
      Atherosclerosis
      Bcl-Associated Death Protein
      Bone Marrow Cells
      Bone Marrow Transplantation
      Cell Survival
      Cells, Cultured
      Diet, High-Fat
      Disease Models, Animal
      Endoplasmic Reticulum Stress
      Genetic Predisposition to Disease
      Hypercholesterolemia
      Macrophages
      Inbred C57BL
      Knockout
      Mitogen-Activated Protein Kinase 8
      Mitogen-Activated Protein Kinase 9
      Phenotype
      Atherosclerotic
      Protein Kinase Inhibitors
      Proto-Oncogene Proteins c-akt
      PTEN Phosphohydrolase
      Receptors
      Signal Transduction
      Permalink
      http://hdl.handle.net/11693/37164
      Published Version (Please cite this version)
      http://dx.doi.org/10.1161/ATVBAHA.116.307580
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