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Adenovirus-mediated over-expression of the cyclin/cyclin-dependent kinase inhibitor, p21 inhibits vascular smooth muscle cell proliferation and neointima formation in the rat carotid artery model of balloon angioplasty.
- Source :
-
The Journal of clinical investigation [J Clin Invest] 1995 Nov; Vol. 96 (5), pp. 2260-8. - Publication Year :
- 1995
-
Abstract
- Vascular smooth muscle cell (VSMC) proliferation after arterial injury is important in the pathogenesis of a number of vascular proliferative disorders, including atherosclerosis and restenosis after balloon angioplasty. Thus, a better understanding of the molecular mechanisms underlying VSMC proliferation in response to arterial injury would have important therapeutic implications for patients with atherosclerotic vascular disease. The p21 protein is a negative regulator of mammalian cell cycle progression that functions both by inhibiting cyclin dependent kinases (CDKs) required for the initiation of S phase, and by binding to and inhibiting the DNA polymerase delta co-factor, proliferating cell nuclear antigen (PCNA). In this report, we show that adenovirus-mediated over-expression of human p21 inhibits growth factor-stimulated VSMC proliferation in vitro by efficiently arresting VSMCs in the G1 phase of the cell cycle. This p21-associated cell cycle arrest is associated both with significant inhibition of the phosphorylation of the retinoblastoma gene product (Rb) and with the formation of complexes between p21 and PCNA in VSMCs. In addition, we demonstrate that localized arterial infection with a p21-encoding adenovirus at the time of balloon angioplasty significantly reduced neointimal hyperplasia in the rat carotid artery model of restenosis. Taken together, these studies demonstrate the important role of p21 in regulating Rb phosphorylation and cell cycle progression in VSMC, and suggest a novel cytostatic gene therapy approach for restenosis and related vascular proliferative disorders.
- Subjects :
- Animals
Cell Division drug effects
Cell Transformation, Viral
Cells, Cultured
Cyclin-Dependent Kinase Inhibitor p21
Cyclin-Dependent Kinases antagonists & inhibitors
Cyclins pharmacology
Enzyme Inhibitors pharmacology
Hyperplasia
Male
Muscle, Smooth, Vascular virology
Rats
Rats, Sprague-Dawley
Tunica Intima pathology
Adenoviridae
Angioplasty, Balloon adverse effects
Cyclins biosynthesis
Muscle, Smooth, Vascular metabolism
Muscle, Smooth, Vascular pathology
Subjects
Details
- Language :
- English
- ISSN :
- 0021-9738
- Volume :
- 96
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- The Journal of clinical investigation
- Publication Type :
- Academic Journal
- Accession number :
- 7593612
- Full Text :
- https://doi.org/10.1172/JCI118281