Abstract 15960: Macrophage IKKalpha Deficiency Suppresses Akt Phosphorylation, Reduces Cell Survival and Decreases Early Atherosclerosis
Macrophages are uniquely resistant to pro-apoptotic stimuli in the toxic environment of atheromatous plaques. Two major pathways, PI3K/Akt and NF-κB, are crucial for generating pro-survival signaling. IKKα is a member of the IκB kinase complex that activates the NF-κB transcription factor and also associated with the Akt pathway. However, the role of IKKα in macrophage survival and atherosclerosis remains unclear. Since IKKα-/- mice die soon after birth, we used the fetal liver cell (FLC) transplantation approach to examine the impact of IKKα deficiency on macrophage survival in vitro and the development of atherosclerosis in LDLR-/- mice in vivo. Here we demonstrate that IKKα deficiency in mouse macrophages significantly suppresses Akt S473 phosphorylation. This was accompanied by suppression of mTORC2 signaling targets including the activity of serum- and glucocorticoid-induced protein kinase (SGK) and its down-stream effector protein kinase C alpha (PKCalpha). Similar suppression of p-SGK and p-PKCalpha was induced in wild-type (WT) macrophages by prolonged treatment with rapamycin, which is known to impair mTORC2 assembly. Compared to WT cells, Akt signaling in IKKα-/- macrophages was significantly down-regulated in response to ER stress and this markedly decreased cell resistance to several different pro-apoptotic stimuli. In vivo, IKKα hematopoietic cell deficiency increased macrophage apoptosis in atherosclerotic lesions and decreased early atherosclerosis by 45% and 63% in female and male LDLR-/- mice reconstituted with IKKα-/- FLC cells, respectively, compared to control LDLR-/- mice transplanted with WT FLC cells. We conclude that IKKα deficiency in mouse macrophages significantly suppresses Akt S473 activity and this diminishes cell survival, resulting in increased macrophage apoptosis and reduced early atherosclerotic lesions in LDLR-/- mice.
- © 2013 by American Heart Association, Inc.