Prevention of graft coronary arteriosclerosis by antisense cdk2 kinase oligonucleotide

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Abstract
Graft coronary arteriosclerosis, which limits the long-term survival of allograft recipients, is characterized by diffuse intimal thickening composed of proliferative smooth muscle cells1,2. 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 allo-grafts. 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 neointi-mal 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.

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