Genetic engineering of vein grafts resistant to atherosclerosis.
Previously, researchers have speculated that genetic engineering can improve the long-term function of vascular grafts which are prone to atherosclerosis and occlusion. In this study, we demonstrated that an intraoperative gene therapy approach using antisense oligodeoxynucleotide blockage of medial smooth muscle cell proliferation can prevent the accelerated atherosclerosis that is responsible for autologous vein graft failure. Selective blockade of the expression of genes for two cell cycle regulatory proteins, proliferating cell nuclear antigen and cell division cycle 2 kinase, was achieved in the smooth muscle cells of rabbit jugular veins grafted into the carotid arteries. This alteration of gene expression successfully redirected vein graft biology away from neointimal hyperplasia and toward medial hypertrophy, yielding conduits that more closely resembled normal arteries. More importantly, these genetically engineered grafts proved resistant to diet-induced atherosclerosis. These findings establish the feasibility of developing genetically engineered bioprostheses that are resistant to failure and better suited to the long-term treatment of occlusive vascular disease.
Mann
M J
MJ
Division of Cardiovascular Medicine, Falk Cardiovascular Research Center, Stanford University School of Medicine, CA 94305, USA.
Gibbons
G H
GH
Kernoff
R S
RS
Diet
F P
FP
Tsao
P S
PS
Cooke
J P
JP
Kaneda
Y
Y
Dzau
V J
VJ
D000818:Animals; D001011:Aorta / Q000166:cytology* / Q000378:metabolism; D001161:Arteriosclerosis / Q000235:genetics / Q000517:prevention & control*; D001483:Base Sequence; D016203:CDC2 Protein Kinase / Q000096:biosynthesis / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D017690:Cell Transplantation; D005818:Genetic Engineering; D006801:Humans; D008969:Molecular Sequence Data; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D018809:Proliferating Cell Nuclear Antigen / Q000096:biosynthesis / Q000378:metabolism; D011817:Rabbits; D014162:Transfection; D017539:Tunica Intima / Q000166:cytology / Q000378:metabolism; D014656:Vascular Surgical Procedures
D016376:Oligonucleotides, Antisense; D018809:Proliferating Cell Nuclear Antigen; D016203:CDC2 Protein Kinase