Cell cycle inhibition preserves endothelial function in genetically engineered rabbit vein grafts.
Journal Article (Journal Article)
We have recently shown that ex vivo gene therapy of rabbit autologous vein grafts with antisense oligodeoxynucleotides (AS ODN) blocking cell cycle regulatory gene expression inhibits not only neointimal hyperplasia, but also diet-induced, accelerated graft atherosclerosis. We observed that these grafts remained free of macrophage invasion and foam cell deposition. Since endothelial dysfunction plays an important role in vascular disease, the current study examined the effect of this genetic engineering strategy on graft endothelial function and its potential relationship to the engineered vessels' resistance to atherosclerosis. Rabbit vein grafts transfected with AS ODN against proliferating cell nuclear antigen (PCNA) and cell division cycle 2 (cdc2) kinase elaborated significantly more nitric oxide and exhibited greater vasorelaxation to both calcium ionophore and acetylcholine than did untreated or control ODN-treated grafts. This preservation of endothelial function was associated with a reduction in superoxide radical generation, vascular cell adhesion molecule-1 (VCAM-1) expression, and monocyte binding activity in grafts in both normal and hypercholesterolemic rabbits. Our data demonstrate that AS ODN arrest of vascular cell cycle progression results in the preservation of normal endothelial phenotype and function, thereby influencing the biology of the vessel wall towards a reduction of its susceptibility to occlusive disease.
Full Text
Duke Authors
Cited Authors
- Mann, MJ; Gibbons, GH; Tsao, PS; von der Leyen, HE; Cooke, JP; Buitrago, R; Kernoff, R; Dzau, VJ
Published Date
- March 15, 1997
Published In
Volume / Issue
- 99 / 6
Start / End Page
- 1295 - 1301
PubMed ID
- 9077539
Pubmed Central ID
- PMC507945
International Standard Serial Number (ISSN)
- 0021-9738
Digital Object Identifier (DOI)
- 10.1172/JCI119288
Language
- eng
Conference Location
- United States