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



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.



Loss of Jnk1, but not Jnk2, in macrophages protects them from apoptosis, increasing cell survival, and this accelerates early atherosclerosis.
From the Departments of Medicine (V.R.B., M.Y., L.D., Y.Z., J.M.M., M.F.L.) and Pharmacology (M.F.L.), Vanderbilt University Medical Center, Nashville, TN; Department of Molecular Biology and Genetics, Bilkent University, Ankara, Turkey (E.E.); Department of Medicine, Oregon Health & Science University, Portland, OR (S.F.); and Department of Genetics & Complex Diseases & Sabri Ulker Center, Harvard School of Public Health, Boston, MA (G.S.H.). vladimir.babaev@vanderbilt.edu macrae.linton@vanderbilt.edu.
Vladimir R
VR
Babaev
From the Departments of Medicine (V.R.B., M.Y., L.D., Y.Z., J.M.M., M.F.L.) and Pharmacology (M.F.L.), Vanderbilt University Medical Center, Nashville, TN; Department of Molecular Biology and Genetics, Bilkent University, Ankara, Turkey (E.E.); Department of Medicine, Oregon Health & Science University, Portland, OR (S.F.); and Department of Genetics & Complex Diseases & Sabri Ulker Center, Harvard School of Public Health, Boston, MA (G.S.H.).
Michele
M
Yeung
From the Departments of Medicine (V.R.B., M.Y., L.D., Y.Z., J.M.M., M.F.L.) and Pharmacology (M.F.L.), Vanderbilt University Medical Center, Nashville, TN; Department of Molecular Biology and Genetics, Bilkent University, Ankara, Turkey (E.E.); Department of Medicine, Oregon Health & Science University, Portland, OR (S.F.); and Department of Genetics & Complex Diseases & Sabri Ulker Center, Harvard School of Public Health, Boston, MA (G.S.H.).
Ebru
E
Erbay
From the Departments of Medicine (V.R.B., M.Y., L.D., Y.Z., J.M.M., M.F.L.) and Pharmacology (M.F.L.), Vanderbilt University Medical Center, Nashville, TN; Department of Molecular Biology and Genetics, Bilkent University, Ankara, Turkey (E.E.); Department of Medicine, Oregon Health & Science University, Portland, OR (S.F.); and Department of Genetics & Complex Diseases & Sabri Ulker Center, Harvard School of Public Health, Boston, MA (G.S.H.).
Lei
L
Ding
From the Departments of Medicine (V.R.B., M.Y., L.D., Y.Z., J.M.M., M.F.L.) and Pharmacology (M.F.L.), Vanderbilt University Medical Center, Nashville, TN; Department of Molecular Biology and Genetics, Bilkent University, Ankara, Turkey (E.E.); Department of Medicine, Oregon Health & Science University, Portland, OR (S.F.); and Department of Genetics & Complex Diseases & Sabri Ulker Center, Harvard School of Public Health, Boston, MA (G.S.H.).
Youmin
Y
Zhang
From the Departments of Medicine (V.R.B., M.Y., L.D., Y.Z., J.M.M., M.F.L.) and Pharmacology (M.F.L.), Vanderbilt University Medical Center, Nashville, TN; Department of Molecular Biology and Genetics, Bilkent University, Ankara, Turkey (E.E.); Department of Medicine, Oregon Health & Science University, Portland, OR (S.F.); and Department of Genetics & Complex Diseases & Sabri Ulker Center, Harvard School of Public Health, Boston, MA (G.S.H.).
James M
JM
May
From the Departments of Medicine (V.R.B., M.Y., L.D., Y.Z., J.M.M., M.F.L.) and Pharmacology (M.F.L.), Vanderbilt University Medical Center, Nashville, TN; Department of Molecular Biology and Genetics, Bilkent University, Ankara, Turkey (E.E.); Department of Medicine, Oregon Health & Science University, Portland, OR (S.F.); and Department of Genetics & Complex Diseases & Sabri Ulker Center, Harvard School of Public Health, Boston, MA (G.S.H.).
Sergio
S
Fazio
From the Departments of Medicine (V.R.B., M.Y., L.D., Y.Z., J.M.M., M.F.L.) and Pharmacology (M.F.L.), Vanderbilt University Medical Center, Nashville, TN; Department of Molecular Biology and Genetics, Bilkent University, Ankara, Turkey (E.E.); Department of Medicine, Oregon Health & Science University, Portland, OR (S.F.); and Department of Genetics & Complex Diseases & Sabri Ulker Center, Harvard School of Public Health, Boston, MA (G.S.H.).
Gökhan S
GS
Hotamisligil
From the Departments of Medicine (V.R.B., M.Y., L.D., Y.Z., J.M.M., M.F.L.) and Pharmacology (M.F.L.), Vanderbilt University Medical Center, Nashville, TN; Department of Molecular Biology and Genetics, Bilkent University, Ankara, Turkey (E.E.); Department of Medicine, Oregon Health & Science University, Portland, OR (S.F.); and Department of Genetics & Complex Diseases & Sabri Ulker Center, Harvard School of Public Health, Boston, MA (G.S.H.). vladimir.babaev@vanderbilt.edu macrae.linton@vanderbilt.edu.
MacRae F
MF
Linton
D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D001018:Aortic Diseases / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D017209:Apoptosis / Q000187:drug effects; D050197:Atherosclerosis / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D001854:Bone Marrow Cells / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D016026:Bone Marrow Transplantation; D002470:Cell Survival; D002478:Cells, Cultured; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D059865:Endoplasmic Reticulum Stress; D020022:Genetic Predisposition to Disease; D006937:Hypercholesterolemia / Q000201:enzymology / Q000235:genetics; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D048055:Mitogen-Activated Protein Kinase 8 / Q000037:antagonists & inhibitors / Q000172:deficiency* / Q000235:genetics; D048056:Mitogen-Activated Protein Kinase 9 / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics; D051059:PTEN Phosphohydrolase / Q000037:antagonists & inhibitors / Q000378:metabolism; D010641:Phenotype; D058226:Plaque, Atherosclerotic; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011973:Receptors, LDL / Q000172:deficiency* / Q000235:genetics; D015398:Signal Transduction; D051025:bcl-Associated Death Protein / Q000378:metabolism
C494820:Bad protein, mouse; D047428:Protein Kinase Inhibitors; D011973:Receptors, LDL; D051025:bcl-Associated Death Protein; D048056:Mitogen-Activated Protein Kinase 9; D051057:Proto-Oncogene Proteins c-akt; D048055:Mitogen-Activated Protein Kinase 8; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse
MAP kinase signaling system; apoptosis; atherosclerosis; endoplasmic reticulum stress; macrophages