title: Adenoviral RB2/p130 gene transfer inhibits smooth muscle cell proliferation and prevents restenosis after angioplasty.
abstract: Smooth muscle cell (SMC) proliferation that results in neointima formation is implicated in the pathogenesis of atherosclerotic plaques and accounts for the high rates of restenosis that occur after percutaneous transluminal coronary angioplasty, a widespread treatment for coronary artery disease. Endothelial lesions trigger intense proliferative signals to the SMCs of the subintima, stimulating their reentry into the cell cycle from a resting G(0) state, resulting in neointima formation and vascular occlusion. Cellular proliferation is negatively controlled by growth-regulatory or tumor-suppressor genes, or both, such as the retinoblastoma gene family members (RB/p105, p107, RB2/p130). In the present study, we show that RB2/p130 inhibited SMC proliferation in vitro and in vivo. We used the rat carotid artery model of restenosis to demonstrate that adenovirus-mediated localized arterial transduction of RB2/p130 at the time of angioplasty significantly reduced neointimal hyperplasia and prevented restenosis. Furthermore, the ability of pRb2/p130 to block proliferation correlated with its ability to bind and sequester the E2F family of transcription factors, which are important mediators of cell cycle progression. These results imply that RB2/p130 could be an important target for vascular gene therapy.
authors.affiliation: Department of Pathology Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA, USA. pclaudio@lac.jci.tju.edu
authors.forename: P P
authors.initials: PP
authors.lastname: Claudio
authors.forename: L
authors.initials: L
authors.lastname: Fratta
authors.forename: F
authors.initials: F
authors.lastname: Farina
authors.forename: C M
authors.initials: CM
authors.lastname: Howard
authors.forename: G
authors.initials: G
authors.lastname: Stassi
authors.forename: S
authors.initials: S
authors.lastname: Numata
authors.forename: C
authors.initials: C
authors.lastname: Pacilio
authors.forename: A
authors.initials: A
authors.lastname: Davis
authors.forename: M
authors.initials: M
authors.lastname: Lavitrano
authors.forename: M
authors.initials: M
authors.lastname: Volpe
authors.forename: J M
authors.initials: JM
authors.lastname: Wilson
authors.forename: B
authors.initials: B
authors.lastname: Trimarco
authors.forename: A
authors.initials: A
authors.lastname: Giordano
authors.forename: G
authors.initials: G
authors.lastname: Condorelli
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D015906:Angioplasty, Balloon, Coronary; D000818:Animals; D020212:Carotid Artery Injuries / Q000209:etiology / Q000473:pathology; D016893:Carotid Stenosis / Q000473:pathology / Q000517:prevention & control* / Q000628:therapy; D002352:Carrier Proteins; D002404:Catheterization / Q000009:adverse effects*; D002453:Cell Cycle; D018797:Cell Cycle Proteins; D002455:Cell Division; D002478:Cells, Cultured; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D016161:Genes, Retinoblastoma; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000627:therapeutic use*; D009131:Muscle, Smooth, Vascular / Q000473:pathology*; D010750:Phosphoproteins / Q000235:genetics / Q000502:physiology*; D011506:Proteins; D011651:Pulmonary Artery / Q000166:cytology; D051381:Rats; D012008:Recurrence; D056465:Retinoblastoma-Binding Protein 1; D050717:Retinoblastoma-Like Protein p130; D050680:Transcription Factor DP1; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000378:metabolism; D015533:Transcriptional Activation; D017539:Tunica Intima / Q000293:injuries* / Q000378:metabolism; D014945:Wound Healing
chemical_list: D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D010750:Phosphoproteins; D011506:Proteins; C493839:Rbl2 protein, rat; D056465:Retinoblastoma-Binding Protein 1; D050717:Retinoblastoma-Like Protein p130; D050680:Transcription Factor DP1; D014157:Transcription Factors