title: Synergistic role of protein phosphatase inhibitor 1 and sarco/endoplasmic reticulum Ca2+ -ATPase in the acquisition of the contractile phenotype of arterial smooth muscle cells.
abstract: BACKGROUND
  Phenotypic modulation or switching of vascular smooth muscle cells from a contractile/quiescent to a proliferative/synthetic phenotype plays a key role in vascular proliferative disorders such as atherosclerosis and restenosis. Although several calcium handling proteins that control differentiation of smooth muscle cells have been identified, the role of protein phosphatase inhibitor 1 (I-1) in the acquisition or maintenance of the contractile phenotype modulation remains unknown.
  
  
  RESULTS
  In human coronary arteries, I-1 and sarco/endoplasmic reticulum Ca2+ -ATPase expression is specific to contractile vascular smooth muscle cells. In synthetic cultured human coronary artery smooth muscle cells, protein phosphatase inhibitor 1 (I-1 target) is highly expressed, leading to a decrease in phospholamban phosphorylation, sarco/endoplasmic reticulum Ca2+ -ATPase, and cAMP-responsive element binding activity. I-1 knockout mice lack phospholamban phosphorylation and exhibit vascular smooth muscle cell arrest in the synthetic state with excessive neointimal proliferation after carotid injury, as well as significant modifications of contractile properties and relaxant response to acetylcholine of femoral artery in vivo. Constitutively active I-1 gene transfer decreased neointimal formation in an angioplasty rat model by preventing vascular smooth muscle cell contractile to synthetic phenotype change.
  
  
  CONCLUSIONS
  I-1 and sarco/endoplasmic reticulum Ca2+ -ATPase synergistically induce the vascular smooth muscle cell contractile phenotype. Gene transfer of constitutively active I-1 is a promising therapeutic strategy for preventing vascular proliferative disorders.
authors.affiliation: Cardiovascular Research Center. Mount Sinai School of Medicine, New York, NY (L. Lipskaia, J.C., I.C.T., D.J., I.K., A.S.R., L. Liang, S.T.T., J.C.K., R.J.H.., L.H.); INSERM UMRS 956, Université Pierre et Marie Curie-Paris 6, Paris, France (L. Lipskaia, E.M., F.A., A.-M.L.); LIA/Transatlantic Cardiovascular Research Center, Université Pierre et Marie Curie/Mount Sinai School of Medicine, New York, NY (L. Lipskaia, J.C., I.C.T., E.M., D.J., I.K., L. Liang, F.A., A.-M.L., S.T.T., J.C.K., R.J.H., L.H.); INSERM U770, University Paris Sud, Le Kremlin-Bicêtre, France (R.B., J.J.L.); PECMV-Université Pierre et Marie Curie-Paris, Paris, France (N.M.); and University of Cincinnati, Cincinnati, OH (E.K.).
authors.forename: Larissa
authors.initials: L
authors.lastname: Lipskaia
authors.forename: Regis
authors.initials: R
authors.lastname: Bobe
authors.forename: Jiqiu
authors.initials: J
authors.lastname: Chen
authors.forename: Irene C
authors.initials: IC
authors.lastname: Turnbull
authors.forename: Jose J
authors.initials: JJ
authors.lastname: Lopez
authors.forename: Elise
authors.initials: E
authors.lastname: Merlet
authors.forename: Dongtaq
authors.initials: D
authors.lastname: Jeong
authors.forename: Ioannis
authors.initials: I
authors.lastname: Karakikes
authors.forename: Alexandra S
authors.initials: AS
authors.lastname: Ross
authors.forename: Lifan
authors.initials: L
authors.lastname: Liang
authors.forename: Nathalie
authors.initials: N
authors.lastname: Mougenot
authors.forename: Fabrice
authors.initials: F
authors.lastname: Atassi
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Lompré
authors.forename: Sima T
authors.initials: ST
authors.lastname: Tarzami
authors.forename: Jason C
authors.initials: JC
authors.lastname: Kovacic
authors.forename: Evangelia
authors.initials: E
authors.lastname: Kranias
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Hajjar
authors.forename: Lahouaria
authors.initials: L
authors.lastname: Hadri
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000166:cytology / Q000502:physiology; D020013:Calcium Signaling / Q000502:physiology; D003331:Coronary Vessels / Q000166:cytology / Q000502:physiology; D005263:Femoral Artery / Q000166:cytology / Q000502:physiology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008323:Mammary Arteries / Q000166:cytology / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism*; D010641:Phenotype; D054645:Protein Phosphatase 1 / Q000235:genetics / Q000378:metabolism*; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000235:genetics / Q000378:metabolism*; D014652:Vascular Diseases / Q000235:genetics / Q000378:metabolism; D014661:Vasoconstriction / Q000502:physiology*
chemical_list: C506948:Atp2a2 protein, rat; D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; C021042:protein phosphatase inhibitor-1; C472592:protein phosphatase inhibitor-1, rat; C517187:PPP1CA protein, human; D054645:Protein Phosphatase 1; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; C506946:ATP2A2 protein, human; C506947:Atp2a2 protein, mouse
keywords: calcium; gene therapy; muscle, smooth; restenosis; vascular diseases