Prevention of graft coronary arteriosclerosis by antisense cdk2 kinase oligonucleotide.
Graft coronary arteriosclerosis, which limits the long-term survival of allograft recipients, is characterized by diffuse intimal thickening composed of proliferative smooth muscle cells. We observed that messenger RNA of the cell cycle regulatory enzyme cyclin-dependent kinase (cdk) 2 kinase, which mediates smooth muscle cell proliferation, was elevated in the thickened intima of coronary arteries of murine heterotopic cardiac allografts. We studied the effects of antisense phosphorothioate oligodeoxynucleotide (ODN) against this enzyme using gene transfer mediated by a hemagglutinating virus of Japan (HVJ)-liposome complex intraluminally delivered to inhibit the intimal hyperplasia. At 30 days after transplantation, antisense cdk2 kinase ODN treatment had dramatically inhibited neointimal formation in the allografts. Expression of vascular cell adhesion molecule-1 was also suppressed by antisense cdk2 kinase. However, these effects were not observed in the sense or scrambled ODN-treated allografts. Thus, an intraluminal administration of antisense ODN directed to a specific cell cycle regulatory gene can inhibit neointimal formation after cardiac transplantation.
Suzuki
J
J
First Department of Internal Medicine, Shinshu University School of Medicine, Matsumoto, Nagano, Japan.
Isobe
M
M
Morishita
R
R
Aoki
M
M
Horie
S
S
Okubo
Y
Y
Kaneda
Y
Y
Sawa
Y
Y
Matsuda
H
H
Ogihara
T
T
Sekiguchi
M
M
D000818:Animals; D042846:CDC2-CDC28 Kinases; D003324:Coronary Artery Disease / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D003331:Coronary Vessels / Q000201:enzymology / Q000473:pathology; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases / Q000235:genetics*; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D006086:Graft vs Host Disease / Q000517:prevention & control*; D016027:Heart Transplantation / Q000009:adverse effects*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D016376:Oligonucleotides, Antisense / Q000378:metabolism / Q000627:therapeutic use*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018108:Respirovirus / Q000235:genetics
D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; C495893:Cdk2 protein, mouse; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases