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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 −/− , andJnk2 −/− 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 orJnk2 −/− cells. Moreover, genetic ablation of JNK to a single allele (Jnk1 +/− /Jnk2 −/− orJnk1 −/− /Jnk2 +/− ) in marrow ofLdlr −/− recipients further increased atherosclerosis compared withJnk1 −/− →Ldlr −/− and wild-type→Ldlr −/− mice. In mouse macrophages, anisomycin-mediated JNK signaling antagonized Akt activity, and loss ofJnk1 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 inJnk1 −/− 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 ofJnk1 , but notJnk2 , in macrophages protects them from apoptosis, increasing cell survival, and this accelerates early atherosclerosis.

arteriosclerosis, thrombosis, and vascular biology

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

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