title: Akt controls vascular smooth muscle cell proliferation in vitro and in vivo by delaying G1/S exit.
abstract: Constitutive activation of serine/threonine kinase Akt causes uncontrolled cell-cycle progression in different cell types and in malignancy. To investigate how Akt activation modulates cell-cycle progression in vascular smooth muscle cells (SMCs) in vitro and in the intact animal, we inhibited Akt-dependent signaling by adenovirus-mediated transfection of a dominant-negative Akt mutant (AA-Akt). We observed reduced proliferation rate (P<0.01), DNA synthesis (P<0.01), and a significant arrest in G1/S exit (P<0.01) both in vitro in response to serum stimulation and in vivo after vascular injury. In vivo transfection of the balloon-injured vessel with AA-Akt reduced SMC proliferation, resulting in decreased neointima compared with control virus (P<0.01). These effects were at least in part modulated, both in vitro and in vivo, by increased p21Cip1 expression, as demonstrated by lack of effect of AA-Akt on cell proliferation in p21-/- mouse SMCs. In conclusion, this study demonstrates that Akt-dependent signaling enhances cell-cycle progression of nontransformed SMCs in vitro and in response to vascular injury in the intact animal. These results suggest a role for Akt signaling in modulating the response of normal tissues to stress and the response of the arterial wall to acute and possibly repetitive injuries that ultimately contribute to restenosis and atherosclerosis.
authors: Cardiovascular Research Institute, Washington Hospital Center, 110 Irving St NW, 4B-1, Washington, DC 20010, USA. geko50@katamail.com
authors: Eugenio
authors: E
authors: Stabile
authors: Yi Fu
authors: YF
authors: Zhou
authors: Motoyasu
authors: M
authors: Saji
authors: Marco
authors: M
authors: Castagna
authors: Matie
authors: M
authors: Shou
authors: Timothy D
authors: TD
authors: Kinnaird
authors: Richard
authors: R
authors: Baffour
authors: Matthew D
authors: MD
authors: Ringel
authors: Stephen E
authors: SE
authors: Epstein
authors: Shmuel
authors: S
authors: Fuchs
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000800:Angioplasty, Balloon / Q000009:adverse effects; D000818:Animals; D001798:Blood Proteins / Q000494:pharmacology; D016893:Carotid Stenosis / Q000209:etiology / Q000473:pathology / Q000628:therapy; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D016193:G1 Phase / Q000502:physiology*; D005799:Genes, Dominant; D015316:Genetic Therapy / Q000379:methods; D006083:Graft Occlusion, Vascular / Q000209:etiology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D017207:Rats, Sprague-Dawley; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D016196:S Phase / Q000187:drug effects / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology
chemical_list: D001798:Blood Proteins; C493957:Cdkn1a protein, mouse; C493958:Cdkn1a protein, rat; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D011518:Proto-Oncogene Proteins; C494920:Akt1 protein, rat; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa