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(Circulation Research. 1999;85:1032.)
© 1999 American Heart Association, Inc.

Integrative Physiology

Adenoviral RB2/p130 Gene Transfer Inhibits Smooth Muscle Cell Proliferation and Prevents Restenosis After Angioplasty

Pier Paolo Claudio, Luigi Fratta, Felicia Farina, Candace M. Howard, Giorgio Stassi, Shin-ichiro Numata, Carmen Pacilio, Alan Davis, Marialuisa Lavitrano, Massimo Volpe, James M. Wilson, Bruno Trimarco, Antonio Giordano, Gianluigi Condorelli

From the Department of Pathology Anatomy and Cell Biology (P.P.C., C.M.H., C.P., A.G.) and Kimmel Cancer Center (G.C.), Thomas Jefferson University, Philadelphia, Pa; Dipartimento di Scienze Odontostomatologiche e Maxillo-Facciali (P.P.C.), Universitá degli Studi di Napoli "Federico II," Napoli, Italy; IRCCS "Neuromed" Institute (L.F., M.V., B.T.), Pozzilli (IS), Italy; Rangos Research Center (G.S.), University of Pittsburgh, Pittsburgh, Pa; Department of Surgical, Anatomical and Oncological Sciences (F.F., G.S.), Human Anatomy Section, University of Palermo, Palermo, Italy; Institute for Human Gene Therapy (A.D., J.M.W.), Departments of Medicine and Molecular and Cellular Engineering, University of Pennsylvania and the Wistar Institute, Philadelphia; Department of Experimental Medicine and Pathology (M.L., M.V., G.C.), University "La Sapienza" Medical School, Rome, Italy; and Department of Medicine (B.T.), University "Federico II" Medical School, Naples, Italy.

Correspondence to Pier Paolo Claudio, MD, PhD, 1020 Locust St, Room 226, Philadelphia, PA 19107, or Gianluigi Condorelli, MD, PhD, 233 S 10th St, Room 1006, Philadelphia, PA 19107. E-mail pclaudio@lac.jci.tju.edu or condore1{at}jeflin.tju.edu

Abstract—Smooth muscle cell (SMC) proliferation that results in neointima formation is implicated in the pathogenesis of atherosclerotic plaques and accounts for the high rates of restenosis that occur after percutaneous transluminal coronary angioplasty, a widespread treatment for coronary artery disease. Endothelial lesions trigger intense proliferative signals to the SMCs of the subintima, stimulating their reentry into the cell cycle from a resting G₀ state, resulting in neointima formation and vascular occlusion. Cellular proliferation is negatively controlled by growth-regulatory or tumor-suppressor genes, or both, such as the retinoblastoma gene family members (RB/p105, p107, RB2/p130). In the present study, we show that RB2/p130 inhibited SMC proliferation in vitro and in vivo. We used the rat carotid artery model of restenosis to demonstrate that adenovirus-mediated localized arterial transduction of RB2/p130 at the time of angioplasty significantly reduced neointimal hyperplasia and prevented restenosis. Furthermore, the ability of pRb2/p130 to block proliferation correlated with its ability to bind and sequester the E2F family of transcription factors, which are important mediators of cell cycle progression. These results imply that RB2/p130 could be an important target for vascular gene therapy.

Key Words: restenosis • adenovirus • cell cycle • pRb2 • p130 • gene therapy

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