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(Circulation. 2000;101:1447.)
© 2000 American Heart Association, Inc.

Basic Science Reports

Transfection of Antisense p53 Tumor Suppressor Gene Oligodeoxynucleotides Into Rat Carotid Artery Results in Abnormal Growth of Vascular Smooth Muscle Cells

Hidetsugu Matsushita, MD; Ryuichi Morishita, MD, PhD; Motokuni Aoki, MD, PhD; Naruya Tomita, MD, PhD; Yoshiaki Taniyama, MD; Hironori Nakagami, MD; Takashi Shimozato, BS; Jitsuo Higaki, MD, PhD; Yasufumi Kaneda, MD, PhD; Toshio Ogihara, MD, PhD

From the Department of Geriatric Medicine, Osaka University Medical School, Suita 565, Japan (H.M., R.M., M.A., N.T., Y.T., H.N., J.H., T.O.); Kankyou Bilis, Shiga, Japan (T.S.); and the Division of Gene Therapy Science, Osaka University Medical School, Suita 565, Japan (R.M., Y.K.).

Correspondence to Ryuichi Morishita, MD, PhD, Division of Gene Therapy Science, Osaka University Medical School, 2-2 Yamada-oka, Suita 565, Japan. E-mail morishit{at}geriat.med.osaka-u.ac.jp

Background—Although loss of activity of an antioncogene, the p53 tumor suppressor gene product, has been postulated in the pathogenesis of human restenosis, little is known about the role of p53 in the regulation of vascular smooth muscle cell (VSMC) growth. In this study, to clarify the role of p53 in the pathogenesis of restenosis, we examined transfection of antisense p53 oligodeoxynucleotides (ODN) into VSMC in vitro and rat carotid artery in vivo.

Methods and Results—The specificity of antisense p53 ODN was confirmed by a significant decrease in p53 protein. Transfection of antisense p53 ODN into VSMC resulted in a significant increase in DNA synthesis and cell number as compared with sense and scrambled ODN (P<0.01). Importantly, transfection of antisense p53 ODN into rat intact carotid artery resulted in a significant increase in the ratio of neointima to medial area at 2 and 4 weeks after transfection, accompanied by a significant decrease in p53 protein (P<0.01). Moreover, cotransfection of wild-type p53 plasmid completely abolished neointimal formation induced by antisense p53 ODN. The sustained effect of a single antisense ODN administration was confirmed by the kinetics of ODN in the vessel wall with the use of FITC-labeled ODN.

Conclusions—Overall, the present study demonstrated that loss of p53 by antisense p53 ODN resulted in an abnormal VSMC growth in vitro and in vivo. These results demonstrated the potential contribution of p53 to the pathogenesis of restenosis.

Key Words: restenosis • muscle, smooth • apoptosis • cells • genes

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