title: Enhancement of Fas ligand-induced inhibition of neointimal formation in rabbit femoral and iliac arteries by coexpression of p35.
abstract: Adenovirus-mediated gene transfer of Fas ligand (FasL) inhibits neointimal formation in balloon-injured rat carotid arteries. Vascular smooth muscle (VSM) cells coexpressing murine FasL and p35, a baculovirus gene that inhibits caspase activity, are not susceptible to FasL-mediated apoptosis in vitro but are capable of inducing apoptosis of VSM cells that do not express p35. We reasoned that coexpression of p35 in FasL-transduced VSM cells in vivo would promote their survival, enhance FasL-induced apoptosis of adjacent VSM cells, and thereby facilitate a greater inhibition of neointimal formation. In balloon-injured rabbit femoral arteries, either Ad2/FasL/p35 or Ad2/FasL was infused into the injured site and withdrawn 20 min later. Both vectors induced a dose-dependent reduction (p < 0.05) of the neointima-to-media ratio when assessed 14 days later. However, Ad2/FasL/p35 exhibited a significantly greater inhibition of neointimal formation than Ad2/FasL. In a more clinically relevant model of restenosis, rabbit iliac arteries were injured with an angioplasty catheter under fluoroscopic guidance. Adenoviral vectors were delivered locally to the injured site over a period of 2 min, using a porous infusion balloon catheter. Twenty-eight days after gene transfer angiographic and histologic assessments indicated a significant (p < 0.05) inhibition of iliac artery lumen stenosis and neointimal formation by Ad2/FasL/p35 (5 x 10(11) particles per artery). The extent of inhibition was comparable to that achieved with Ad2/TK, an adenoviral vector encoding thymidine kinase (5 x 10(11) particles per artery) and coadministration of ganciclovir for 7 days. These data suggest that coexpression of p35 in FasL-transduced VSM cells is more potent at inhibiting neointimal formation and as such represents an improved gene therapy approach for restenosis.
authors.affiliation: Genzyme Corporation, 31 New York Avenue, Framingham, MA 01701, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Luo
authors.forename: T
authors.initials: T
authors.lastname: Garron
authors.forename: M
authors.initials: M
authors.lastname: Palasis
authors.forename: H
authors.initials: H
authors.lastname: Lu
authors.forename: A J
authors.initials: AJ
authors.lastname: Belanger
authors.forename: A
authors.initials: A
authors.lastname: Scaria
authors.forename: K A
authors.initials: KA
authors.lastname: Vincent
authors.forename: T
authors.initials: T
authors.lastname: Date
authors.forename: G Y
authors.initials: GY
authors.lastname: Akita
authors.forename: S H
authors.initials: SH
authors.lastname: Cheng
authors.forename: J
authors.initials: J
authors.lastname: Barry
authors.forename: R J
authors.initials: RJ
authors.lastname: Gregory
authors.forename: C
authors.initials: C
authors.lastname: Jiang
mesh_terms: D000260:Adenoviruses, Human; D000818:Animals; D017209:Apoptosis; D021721:Balloon Occlusion; D023903:Coronary Restenosis / Q000517:prevention & control*; D015853:Cysteine Proteinase Inhibitors; D053222:Fas Ligand Protein; D005263:Femoral Artery / Q000293:injuries* / Q000473:pathology; D015870:Gene Expression; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D006801:Humans; D007083:Iliac Artery / Q000293:injuries* / Q000473:pathology; D051034:Inhibitor of Apoptosis Proteins; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics*; D011817:Rabbits; D013937:Thymidine Kinase / Q000235:genetics; D017539:Tunica Intima / Q000473:pathology; D014764:Viral Proteins / Q000235:genetics*
chemical_list: D015853:Cysteine Proteinase Inhibitors; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505662:Faslg protein, rat; D051034:Inhibitor of Apoptosis Proteins; D008562:Membrane Glycoproteins; D014764:Viral Proteins; C086430:inhibitor of apoptosis, Nucleopolyhedrovirus; D013937:Thymidine Kinase