© 2000 by European Society of Cardiology
Copyright © 2000, European Society of Cardiology
Adenovirus-encoded hammerhead ribozyme to Bcl-2 inhibits neointimal hyperplasia and induces vascular smooth muscle cell apoptosis
aDivision of Cardiovascular Research, St. Elizabeth's Medical Center, Tufts University School of Medicine, 736 Cambridge St., Boston, MA 02135, USA
bProgram in Cell, Molecular and Developmental Biology, Sackler School of Biomedical Studies, Tufts University, 136 Harrison Ave., Boston, MA 02111, USA
cDivision of Urologic Oncology, Department of Urology, Columbia Presbyterian Medical Center, 680 West 168th Street, New York, NY 10033, USA
* Corresponding author. Tel.: +1-617-562-7501; fax: +1-617-562-7506 kwalsh{at}opal.tufts.edu
Objective: The balance between apoptosis and cell proliferation is vital for cellular homeostasis, yet little is known about the mechanisms that coordinate these two cell fates, particularly in the vessel wall. It is well established that the members of Bcl-2-gene family are regulators of apoptosis, but their role in cellular proliferation is less clear. Methods: We analyzed the effects of disrupting Bcl-2 expression in vascular smooth muscle cells (VSMCs) by adenoviral-mediated delivery of a hammerhead ribozyme against bcl-2 mRNA (Ad-Rbz-Bcl-2). Results: Forced ablation of Bcl-2 in balloon-injured rat carotid arteries reduced cell number and inhibited neointimal hyperplasia. In vitro, VSMCs transduced with the Ad-Rbz-Bcl-2 underwent apoptosis as indicated by a reduction in cell number and DNA fragmentation. Ad-Rbz-Bcl-2-transduced cells also exhibited aberrations in both G1- and S-phases of the cell cycle. However, forced perturbations in cell cycle activity by serum-stimulation or treatment with chemical inhibitors did not affect Ad-Rbz-Bcl-2-induced cell death, indicating that these cell cycle changes are not essential for apoptosis. Conclusion: These data show that physiological levels of Bcl-2 are essential for VSMC viability and that ablation of Bcl-2 alters cell cycle activity through the execution of the apoptotic process.
KEYWORDS Apoptosis; Gene therapy; Gene expression; Restenosis; Smooth muscle; Angioplasty
1 Present Address: Northwestern Medical Center, Division of Rheumatology, 745 North Fairbanks Court, Tarry 3-770, Chicago, IL 60611, USA.
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