| First Author | Babaev VR | Year | 2016 |
| Journal | Arterioscler Thromb Vasc Biol | Volume | 36 |
| Issue | 4 | Pages | 598-607 |
| PubMed ID | 26848161 | Mgi Jnum | J:246067 |
| Mgi Id | MGI:5920928 | Doi | 10.1161/ATVBAHA.115.306931 |
| Citation | Babaev VR, et al. (2016) Macrophage IKKalpha Deficiency Suppresses Akt Phosphorylation, Reduces Cell Survival, and Decreases Early Atherosclerosis. Arterioscler Thromb Vasc Biol 36(4):598-607 |
| abstractText | OBJECTIVE: The IkappaB kinase (IKK) is an enzyme complex that initiates the nuclear factor kappaB transcription factor cascade, which is important in regulating multiple cellular responses. IKKalpha is directly associated with 2 major prosurvival pathways, PI3K/Akt and nuclear factor kappaB, but its role in cell survival is not clear. Macrophages play critical roles in the pathogenesis of atherosclerosis, yet the impact of IKKalpha signaling on macrophage survival and atherogenesis remains unclear. APPROACH AND RESULTS: Here, we demonstrate that genetic IKKalpha 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, IKKalpha 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 IKKalpha(-/-) monocytes and macrophages to different proapoptotic stimuli compared with wild-type cells. In vivo, IKKalpha deficiency increased macrophage apoptosis in atherosclerotic lesions and decreased early atherosclerosis in both female and male low-density lipoprotein receptor (LDLR)(-/-) mice reconstituted with IKKalpha(-/-) hematopoietic cells and fed with the Western diet for 8 weeks compared with control LDLR(-/-) mice transplanted with wild-type cells. CONCLUSIONS: Hematopoietic IKKalpha deficiency in mouse suppresses Akt signaling, compromising monocyte/macrophage survival and this decreases early atherosclerosis. |
