Inhibition of vascular smooth muscle cell proliferation and intimal hyperplasia by gene transfer of β-interferon

Background: Balloon injury of the arterial wall induces increased vascular smooth cell proliferation, enhanced elastic recoil, and abnormalities in thrombosis, each of which contribute to regrowth of intima and the lesion of restenosis. Several gene transfer approaches have been used to inhibit such intimal smooth muscle cell growth. In this report, adenoviral gene transfer of β-interferon (β-IFN) was analyzed in a porcine model of balloon injury to determine whether a secreted growth inhibitory protein might affect the regrowth of vascular smooth muscle cells in vitro and in arteries. Materials and Methods: An adenoviral vector encoding β-interferon (ADV-β-IFN) was prepared and used to infect porcine vascular smooth muscle cells in a porcine balloon injury model. Its antiproliferative effect was analyzed in vitro and in vivo. Results: Expression of recombinant porcine β- IFN in vascular smooth muscle cells reduced cell proliferation significantly in vitro, and supernatants derived from the β-IFN vector inhibited vascular smooth muscle cell proliferation relative to controls. When introduced into porcine arteries after balloon injury, a reduction in cell proliferation was observed 7 days after gene transfer measured by BrdC incorporation (ADV-ΔE1 arteries 14.5 ± 1.2%, ADV-β-IFN 6.8 ± 0.8%, p <0.05, unpaired, two- tailed t-test). The intima-to-media area ratio was also reduced (nontransfected arteries, 0.70 ± 0.05; ADV-ΔE1 infected arteries, 0.69 ± 0.06; ADV-β-IFN infected arteries, 0.53 ± 0.03; p <0.05, ANOVA with Dunnett t-test). No evidence of organ toxicity was observed, and regrowth of the endothelial cell surface was observed 3-6 weeks after balloon injury. Conclusions: Gene transfer of an adenoviral vector encoding β-IFN into balloon-injured arteries reduced vascular smooth muscle proliferation and intimal formation. Expression of this gene product may have potential application for the treatment of vascular proliferative diseases.