title: Akt1 regulates vascular smooth muscle cell apoptosis through FoxO3a and Apaf1 and protects against arterial remodeling and atherosclerosis.
abstract: OBJECTIVE
  Vascular smooth muscle cell (VSMC) apoptosis occurs at low levels in atherosclerotic plaques and in vessel remodeling; however, the consequences and mediators of these levels are not known. Akt1 protects against VSMC apoptosis largely through inactivating target proteins such as forkhead class O transcription factor 3a (FoxO3a), but Akt1 signaling is reduced and FoxO3a activity is increased in human atherosclerosis. We therefore sought to determine whether inhibition of VSMC apoptosis via Akt1 activation regulates vessel remodeling and atherogenesis and to identify FoxO3a target proteins that mediate VSMC apoptosis.
  
  
  RESULTS
  We generated mice that express an Akt1 protein that can be activated specifically in arterial VSMCs. Akt1 activation did not affect normal arteries, but inhibited VSMC apoptosis and negative remodeling after carotid ligation, indicating that VSMC apoptosis is a major determinant of vessel caliber after changes in flow. Akt1 activation inhibited VSMC apoptosis during atherogenesis and increased relative fibrous cap area in plaques. Microarray studies identified multiple FoxO3a-regulated genes involved in VSMC apoptosis, including apoptotic protease activating factor 1 as a novel target. Apoptotic protease activating factor 1 mediated the proapoptotic activity of FoxO3a, was increased in human atherosclerosis, but reduced by Akt1 activity in vivo.
  
  
  CONCLUSIONS
  Akt1 is a major regulator of VSMC survival in vivo during vessel remodeling and atherogenesis, mediated in large part through inhibition of FoxO3a and its downstream genes, including apoptotic protease activating factor 1. Our data suggest that even the low-level VSMC apoptosis seen during changes in flow determines vessel wall structure and promotes fibrous cap thinning during atherogenesis.
authors.affiliation: From the Divisions of Cardiovascular Medicine (J.T., H.Y., K.G., N.F., M.B., T.L.), Clinical Pharmacology (J.M.), and Metabolic Research Laboratories (B.L.), University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom; and Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom (T.L.).
authors.forename: Joanna
authors.initials: J
authors.lastname: Tucka
authors.affiliation: From the Divisions of Cardiovascular Medicine (J.T., H.Y., K.G., N.F., M.B., T.L.), Clinical Pharmacology (J.M.), and Metabolic Research Laboratories (B.L.), University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom; and Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom (T.L.).
authors.forename: Haixiang
authors.initials: H
authors.lastname: Yu
authors.affiliation: From the Divisions of Cardiovascular Medicine (J.T., H.Y., K.G., N.F., M.B., T.L.), Clinical Pharmacology (J.M.), and Metabolic Research Laboratories (B.L.), University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom; and Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom (T.L.).
authors.forename: Kelly
authors.initials: K
authors.lastname: Gray
authors.affiliation: From the Divisions of Cardiovascular Medicine (J.T., H.Y., K.G., N.F., M.B., T.L.), Clinical Pharmacology (J.M.), and Metabolic Research Laboratories (B.L.), University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom; and Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom (T.L.).
authors.forename: Nichola
authors.initials: N
authors.lastname: Figg
authors.affiliation: From the Divisions of Cardiovascular Medicine (J.T., H.Y., K.G., N.F., M.B., T.L.), Clinical Pharmacology (J.M.), and Metabolic Research Laboratories (B.L.), University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom; and Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom (T.L.).
authors.forename: Janet
authors.initials: J
authors.lastname: Maguire
authors.affiliation: From the Divisions of Cardiovascular Medicine (J.T., H.Y., K.G., N.F., M.B., T.L.), Clinical Pharmacology (J.M.), and Metabolic Research Laboratories (B.L.), University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom; and Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom (T.L.).
authors.forename: Brian
authors.initials: B
authors.lastname: Lam
authors.affiliation: From the Divisions of Cardiovascular Medicine (J.T., H.Y., K.G., N.F., M.B., T.L.), Clinical Pharmacology (J.M.), and Metabolic Research Laboratories (B.L.), University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom; and Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom (T.L.).
authors.forename: Martin
authors.initials: M
authors.lastname: Bennett
authors.affiliation: From the Divisions of Cardiovascular Medicine (J.T., H.Y., K.G., N.F., M.B., T.L.), Clinical Pharmacology (J.M.), and Metabolic Research Laboratories (B.L.), University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom; and Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom (T.L.). tdl2@cam.ac.uk.
authors.forename: Trevor
authors.initials: T
authors.lastname: Littlewood
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D053477:Apoptotic Protease-Activating Factor 1 / Q000502:physiology*; D050197:Atherosclerosis / Q000503:physiopathology* / Q000517:prevention & control; D002339:Carotid Arteries / Q000503:physiopathology; D002470:Cell Survival / Q000502:physiology; D004195:Disease Models, Animal; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000502:physiology*; D008026:Ligation; D051379:Mice; D008822:Mice, Transgenic; D009131:Muscle, Smooth, Vascular / Q000473:pathology* / Q000503:physiopathology; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D066253:Vascular Remodeling / Q000502:physiology*
chemical_list: C506593:Apaf1 protein, mouse; D053477:Apoptotic Protease-Activating Factor 1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; C514862:Akt1 protein, mouse; D051057:Proto-Oncogene Proteins c-akt
keywords: apoptosis; atherosclerosis