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

Vladimir R. Babaev, Michele Yeung, Ebru Erbay, Lei Ding, Youmin Zhang, James M. May, Sergio Fazio, Gökhan S. Hotamisligil, Mac Rae F Linton

    Research output: Contribution to journalArticle

    15 Citations (Scopus)

    Abstract

    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.

    Original languageEnglish (US)
    JournalArteriosclerosis, Thrombosis, and Vascular Biology
    DOIs
    StateAccepted/In press - Apr 21 2016

    Fingerprint

    JNK Mitogen-Activated Protein Kinases
    LDL Receptors
    Atherosclerosis
    Macrophages
    Apoptosis
    Anisomycin
    Phosphoric Monoester Hydrolases
    Cell Survival
    Pharmacology
    Endoplasmic Reticulum Stress
    Endoplasmic Reticulum
    Protein Isoforms
    Bone Marrow
    Alleles
    Cholesterol
    Diet
    Genes

    ASJC Scopus subject areas

    • Cardiology and Cardiovascular Medicine

    Cite this

    Jnk1 Deficiency in Hematopoietic Cells Suppresses Macrophage Apoptosis and Increases Atherosclerosis in Low-Density Lipoprotein Receptor Null Mice. / Babaev, Vladimir R.; Yeung, Michele; Erbay, Ebru; Ding, Lei; Zhang, Youmin; May, James M.; Fazio, Sergio; Hotamisligil, Gökhan S.; Linton, Mac Rae F.

    In: Arteriosclerosis, Thrombosis, and Vascular Biology, 21.04.2016.

    Research output: Contribution to journalArticle

    Babaev, Vladimir R. ; Yeung, Michele ; Erbay, Ebru ; Ding, Lei ; Zhang, Youmin ; May, James M. ; Fazio, Sergio ; Hotamisligil, Gökhan S. ; Linton, Mac Rae F. / Jnk1 Deficiency in Hematopoietic Cells Suppresses Macrophage Apoptosis and Increases Atherosclerosis in Low-Density Lipoprotein Receptor Null Mice. In: Arteriosclerosis, Thrombosis, and Vascular Biology. 2016.
    @article{fca703edc8634dc299e29bb492da69bd,
    title = "Jnk1 Deficiency in Hematopoietic Cells Suppresses Macrophage Apoptosis and Increases Atherosclerosis in Low-Density Lipoprotein Receptor Null Mice",
    abstract = "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.",
    author = "Babaev, {Vladimir R.} and Michele Yeung and Ebru Erbay and Lei Ding and Youmin Zhang and May, {James M.} and Sergio Fazio and Hotamisligil, {G{\"o}khan S.} and Linton, {Mac Rae F}",
    year = "2016",
    month = "4",
    day = "21",
    doi = "10.1161/ATVBAHA.116.307580",
    language = "English (US)",
    journal = "Arteriosclerosis, Thrombosis, and Vascular Biology",
    issn = "1079-5642",
    publisher = "Lippincott Williams and Wilkins",

    }

    TY - JOUR

    T1 - Jnk1 Deficiency in Hematopoietic Cells Suppresses Macrophage Apoptosis and Increases Atherosclerosis in Low-Density Lipoprotein Receptor Null Mice

    AU - Babaev, Vladimir R.

    AU - Yeung, Michele

    AU - Erbay, Ebru

    AU - Ding, Lei

    AU - Zhang, Youmin

    AU - May, James M.

    AU - Fazio, Sergio

    AU - Hotamisligil, Gökhan S.

    AU - Linton, Mac Rae F

    PY - 2016/4/21

    Y1 - 2016/4/21

    N2 - 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.

    AB - 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.

    UR - http://www.scopus.com/inward/record.url?scp=84964253329&partnerID=8YFLogxK

    UR - http://www.scopus.com/inward/citedby.url?scp=84964253329&partnerID=8YFLogxK

    U2 - 10.1161/ATVBAHA.116.307580

    DO - 10.1161/ATVBAHA.116.307580

    M3 - Article

    JO - Arteriosclerosis, Thrombosis, and Vascular Biology

    JF - Arteriosclerosis, Thrombosis, and Vascular Biology

    SN - 1079-5642

    ER -