Macrophage IKK alpha Deficiency Suppresses Akt Phosphorylation, Reduces Cell Survival, and Decreases Early Atherosclerosis

作者：Babaev Vladimir; Ding Lei; Zhang Youmin; May James M; Lin P Charles; Fazio Sergio; Linton MacRae F

来源：Arteriosclerosis, Thrombosis, and Vascular Biology, 2016, 36(4): 598-607.

DOI：10.1161/ATVBAHA.115.306931

• apoptosis
• atherosclerosis
• cell survival
• macrophages
• phosphorylation

Objective The IB kinase (IKK) is an enzyme complex that initiates the nuclear factor B transcription factor cascade, which is important in regulating multiple cellular responses. IKK is directly associated with 2 major prosurvival pathways, PI3K/Akt and nuclear factor B, but its role in cell survival is not clear. Macrophages play critical roles in the pathogenesis of atherosclerosis, yet the impact of IKK signaling on macrophage survival and atherogenesis remains unclear.
Approach and Results Here, we demonstrate that genetic IKK deficiency, as well as pharmacological inhibition of IKK, in mouse macrophages significantly reduces Akt S-473 phosphorylation, which is accompanied by suppression of mTOR complex 2 signaling. Moreover, IKK null macrophages treated with lipotoxic palmitic acid exhibited early exhaustion of Akt signaling compared with wild-type cells. This was accompanied by a dramatic decrease in the resistance of IKK-/- monocytes and macrophages to different proapoptotic stimuli compared with wild-type cells. In vivo, IKK deficiency increased macrophage apoptosis in atherosclerotic lesions and decreased early atherosclerosis in both female and male low-density lipoprotein receptor (LDLR)(-/-) mice reconstituted with IKK-/- hematopoietic cells and fed with the Western diet for 8 weeks compared with control LDLR-/- mice transplanted with wild-type cells.
Conclusions Hematopoietic IKK deficiency in mouse suppresses Akt signaling, compromising monocyte/macrophage survival and this decreases early atherosclerosis.

• 出版日期2016-4