Jnk1 deficiency in hematopoietic cells suppresses macrophage apoptosis and increases atherosclerosis in low-density lipoprotein receptor null mice
Author(s)
Date
2016Source 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
ArticleItem Usage Stats
183
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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
ApoptosisAtherosclerosis
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/11693/37164Published Version (Please cite this version)
http://dx.doi.org/10.1161/ATVBAHA.116.307580Collections
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