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(Circulation. 1997;96:628-635.)
© 1997 American Heart Association, Inc.
Articles |
Downregulation of Cyclin G1 Expression by Retrovirus-Mediated Antisense Gene Transfer Inhibits Vascular Smooth Muscle Cell Proliferation and Neointima Formation
From the USC Gene Therapy Laboratories (N.L.Z., P.X.L., E.M.G., W.F.A.), the Divisions of Hematology-Oncology (E.M.G.) and Cardiothoracic Surgery (L.W., V.A.S., F.L.H.), and the Departments of Pediatrics (E.M.G., W.F.A.), Biochemistry (W.F.A.), and Surgery (L.W., V.A.S., F.L.H.), Childrens Hospital of Los Angeles, and the University of Southern California School of Medicine, Los Angeles, Calif.
Background The contemporary treatment of coronary athero-occlusive disease by percutaneous transluminal coronary angioplasty is hampered by maladaptive wound healing, resulting in significant failure rates. Morbid sequelae include smooth muscle cell (SMC) hyperplasia and restenosis due to vascular neointima formation.
Methods and Results In this study, we examined the inhibitory effects of a concentrated retroviral vector bearing an antisense cyclin G1 gene on aortic SMC proliferation in vitro and on neointima formation in vivo in a rat carotid injury model of restenosis. Retroviral vectors bearing an antisense cyclin G1 construct inhibited the proliferation of transduced aortic SMCs in 2- to 6-day cultures, concomitant with downregulation of cyclin G1 protein expression and decreased [3H]thymidine incorporation into DNA. Morphological examination showed evidence of cytolysis, giant syncytia formation, and apoptotic changes evidenced by overt cell shrinkage, nuclear fragmentation, and specific immunostaining of nascent 3'-OH DNA ends generated by endonuclease-mediated DNA fragmentation. Pronounced "bystander effects" including neighboring cells were noted in aortic SMCs transduced with the antisense cyclin G1 vector, as determined by quantitative assays and fluorescent labeling of nontransduced cells. In an in vitro tissue injury model, the proliferation and migration of antisense cyclin G1 vector–transduced aortic SMCs were inhibited. Moreover, in vivo delivery of high-titer antisense cyclin G1 vector supernatant to the balloon-injured rat carotid artery in vivo resulted in a significant reduction in neointima formation.
Conclusions These findings represent the first demonstration of the inhibitory effects of an antisense cyclin G1 retroviral vector on nonneoplastic cell proliferation. Taken together, these data affirm the potential utility of antisense cyclin G1 constructs in the development of novel gene therapy approaches to vascular restenosis.
Key Words: angioplasty • muscle, smooth • cyclin G1 • genes
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