title: Macrophage IKKα Deficiency Suppresses Akt Phosphorylation, Reduces Cell Survival, and Decreases Early Atherosclerosis.
abstract: OBJECTIVE
  The IκB kinase (IKK) is an enzyme complex that initiates the nuclear factor κB transcription factor cascade, which is important in regulating multiple cellular responses. IKKα is directly associated with 2 major prosurvival pathways, PI3K/Akt and nuclear factor κB, but its role in cell survival is not clear. Macrophages play critical roles in the pathogenesis of atherosclerosis, yet the impact of IKKα signaling on macrophage survival and atherogenesis remains unclear.
  
  
  RESULTS
  Here, we demonstrate that genetic IKKα 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, IKKα 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 IKKα(-/-) monocytes and macrophages to different proapoptotic stimuli compared with wild-type cells. In vivo, IKKα deficiency increased macrophage apoptosis in atherosclerotic lesions and decreased early atherosclerosis in both female and male low-density lipoprotein receptor (LDLR)(-/-) mice reconstituted with IKKα(-/-) hematopoietic cells and fed with the Western diet for 8 weeks compared with control LDLR(-/-) mice transplanted with wild-type cells.
  
  
  CONCLUSIONS
  Hematopoietic IKKα deficiency in mouse suppresses Akt signaling, compromising monocyte/macrophage survival and this decreases early atherosclerosis.
authors: From the Atherosclerosis Research Unit, Department of Medicine (V.R.B., L.D., Y.Z., J.M.M., M.R.F.L.) and Pharmacology (M.R.F.L.), Vanderbilt University Medical Center, Nashville, TN; Center for Cancer Research, National Cancer Institute, Frederick, MD (P.C.L.); and Department of Medicine, Center of Preventive Cardiology, Oregon Health & Science University, Portland, OR (S.F.). vladimir.babaev@vanderbilt.edu macrae.linton@vanderbilt.edu.
authors: Vladimir R
authors: VR
authors: Babaev
authors: From the Atherosclerosis Research Unit, Department of Medicine (V.R.B., L.D., Y.Z., J.M.M., M.R.F.L.) and Pharmacology (M.R.F.L.), Vanderbilt University Medical Center, Nashville, TN; Center for Cancer Research, National Cancer Institute, Frederick, MD (P.C.L.); and Department of Medicine, Center of Preventive Cardiology, Oregon Health & Science University, Portland, OR (S.F.).
authors: Lei
authors: L
authors: Ding
authors: From the Atherosclerosis Research Unit, Department of Medicine (V.R.B., L.D., Y.Z., J.M.M., M.R.F.L.) and Pharmacology (M.R.F.L.), Vanderbilt University Medical Center, Nashville, TN; Center for Cancer Research, National Cancer Institute, Frederick, MD (P.C.L.); and Department of Medicine, Center of Preventive Cardiology, Oregon Health & Science University, Portland, OR (S.F.).
authors: Youmin
authors: Y
authors: Zhang
authors: From the Atherosclerosis Research Unit, Department of Medicine (V.R.B., L.D., Y.Z., J.M.M., M.R.F.L.) and Pharmacology (M.R.F.L.), Vanderbilt University Medical Center, Nashville, TN; Center for Cancer Research, National Cancer Institute, Frederick, MD (P.C.L.); and Department of Medicine, Center of Preventive Cardiology, Oregon Health & Science University, Portland, OR (S.F.).
authors: James M
authors: JM
authors: May
authors: From the Atherosclerosis Research Unit, Department of Medicine (V.R.B., L.D., Y.Z., J.M.M., M.R.F.L.) and Pharmacology (M.R.F.L.), Vanderbilt University Medical Center, Nashville, TN; Center for Cancer Research, National Cancer Institute, Frederick, MD (P.C.L.); and Department of Medicine, Center of Preventive Cardiology, Oregon Health & Science University, Portland, OR (S.F.).
authors: P Charles
authors: PC
authors: Lin
authors: From the Atherosclerosis Research Unit, Department of Medicine (V.R.B., L.D., Y.Z., J.M.M., M.R.F.L.) and Pharmacology (M.R.F.L.), Vanderbilt University Medical Center, Nashville, TN; Center for Cancer Research, National Cancer Institute, Frederick, MD (P.C.L.); and Department of Medicine, Center of Preventive Cardiology, Oregon Health & Science University, Portland, OR (S.F.).
authors: Sergio
authors: S
authors: Fazio
authors: From the Atherosclerosis Research Unit, Department of Medicine (V.R.B., L.D., Y.Z., J.M.M., M.R.F.L.) and Pharmacology (M.R.F.L.), Vanderbilt University Medical Center, Nashville, TN; Center for Cancer Research, National Cancer Institute, Frederick, MD (P.C.L.); and Department of Medicine, Center of Preventive Cardiology, Oregon Health & Science University, Portland, OR (S.F.).
authors: MacRae F
authors: MF
authors: Linton
mesh_terms: D000818:Animals; D017209:Apoptosis; D050197:Atherosclerosis / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D002470:Cell Survival; D002478:Cells, Cultured; D066273:Diet, Western; D004195:Disease Models, Animal; D005260:Female; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors / Q000172:deficiency* / Q000235:genetics; D018836:Inflammation Mediators / Q000378:metabolism; D008099:Liver / Q000196:embryology / Q000201:enzymology; D016031:Liver Transplantation; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D008297:Male; D000076225:Mechanistic Target of Rapamycin Complex 2; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000378:metabolism; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D013997:Time Factors
chemical_list: D018836:Inflammation Mediators; D046912:Multiprotein Complexes; D047428:Protein Kinase Inhibitors; D011973:Receptors, LDL; D000076225:Mechanistic Target of Rapamycin Complex 2; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase
keywords: apoptosis; atherosclerosis; cell survival; macrophages; phosphorylation