Vladimir R Babaev1, Michele Yeung2, Ebru Erbay2, Lei Ding2, Youmin Zhang2, James M May2, Sergio Fazio2, Gökhan S Hotamisligil2, MacRae F Linton1. 1. 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. 2. 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.).
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.
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.
Authors: Sandeep Robert Datta; Ann M Ranger; Michael Z Lin; James Fitzhugh Sturgill; Yong-Chao Ma; Chris W Cowan; Pieter Dikkes; Stanley J Korsmeyer; Michael E Greenberg Journal: Dev Cell Date: 2002-11 Impact factor: 12.270
Authors: K Sabapathy; Y Hu; T Kallunki; M Schreiber; J P David; W Jochum; E F Wagner; M Karin Journal: Curr Biol Date: 1999-02-11 Impact factor: 10.834
Authors: Nathalie Arbour; Denise Naniche; Dirk Homann; Roger J Davis; Richard A Flavell; Michael B A Oldstone Journal: J Exp Med Date: 2002-04-01 Impact factor: 14.307
Authors: Dietrich Conze; Troy Krahl; Norman Kennedy; Linda Weiss; Joanne Lumsden; Patricia Hess; Richard A Flavell; Graham Le Gros; Roger J Davis; Mercedes Rincón Journal: J Exp Med Date: 2002-04-01 Impact factor: 14.307
Authors: Ozlem Tufanli; Pelin Telkoparan Akillilar; Diego Acosta-Alvear; Begum Kocaturk; Umut Inci Onat; Syed Muhammad Hamid; Ismail Çimen; Peter Walter; Christian Weber; Ebru Erbay Journal: Proc Natl Acad Sci U S A Date: 2017-01-30 Impact factor: 11.205
Authors: MacRae F Linton; Vladimir R Babaev; Jiansheng Huang; Edward F Linton; Huan Tao; Patricia G Yancey Journal: Circ J Date: 2016-10-08 Impact factor: 2.993
Authors: Hong S Lu; Ann Marie Schmidt; Robert A Hegele; Nigel Mackman; Daniel J Rader; Christian Weber; Alan Daugherty Journal: Arterioscler Thromb Vasc Biol Date: 2018-10 Impact factor: 8.311