[Gene transfer of interferon beta inhibits vascular smooth muscle cell proliferation in vitro and in animal model of arterial injury].
Vascular hypertrophy may increase the blood pressure by its effect on vascular resistance. In this study, adenoviral gene transfer of IFN-beta was analysed in a porcine model of balloon injury to determine whether a secreted growth inhibitory protein might affect the regrowth of vascular smooth muscle cells (VSMC) in vitro and in arteries. An adenoviral vector encoding IFN-beta (ADV-IFN-beta) was constructed by homologous recombination between sub360 genomic DNA, an ADV 5 derivative with a deletion in the E3 region and a porcine IFN-beta expression plasmid. Its antiproliferative effect was analysed using cell proliferation assays, and used in a porcine model of balloon injury. After injury, arteries were immediately transfected with 7 x 10(9) plaques forming units of either ADV-IFN-beta or a control E1A deficient adenovirus that does not encode a recombinant protein, ADV-delta E1. The intima/media (I/M) area ratio was determined by quantitative morphometry 21 days after artery injury and gene transfer. Expression of recombinant porcine IFN-beta in VSMC reduced cell proliferation significantly in vitro, and supernatants derived from IFN-beta vector infected cells inhibited VSMC proliferation relative to controls. When introduced into porcine arteries after balloon injury, a reduction in I/M ratio of 30% was found. I/M ratio in the IFN-beta transduced arteries was 0.54 +/- 0.03 vs 0.69 +/- 0.06 in ADV-delta E1 transfected arteries and 0.702 +/- 0.05 in the non-transfected arteries. Gene transfer of an adenoviral vector encoding IFN-beta to VSMC and injured arteries reduced cell proliferation and vascular thickening. This approach is potentially applicable to vascular proliferative diseases.
Stephan
D
D
Institut de pharmacologie, université Louis-Pasteur, Strasbourg.
San
H
H
Gordon
D
D
Nabel
G J
GJ
Nabel
E G
EG
D000818:Animals; D002455:Cell Division / Q000187:drug effects*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000166:cytology* / Q000254:growth & development / Q000293:injuries; D005263:Femoral Artery / Q000293:injuries; D015870:Gene Expression; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D066298:In Vitro Techniques; D016899:Interferon-beta / Q000494:pharmacology*; D024510:Muscle Development; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000254:growth & development / Q000293:injuries; D013552:Swine; D014162:Transfection
D016899:Interferon-beta