Antisense Cdk2 Kinase Oligodeoxynucleotide Inhibits ICAM-1 Expression in Murine Cardiac Allograft Arteriopathy

Abstract

CARDIAC transplantation as a treatment for end-stage cardiac disease has been established. However, the problem of accelerated graft coronary disease in long-term survivors remains. Adhesion molecules play critical roles in graft arteriopathy; that is, intercellular adhesion molecule 1 (ICAM-1) is known to be one of the most important molecules in atherogenesis. Inhibition of arterial neointimal formation by antisense phosphorothioate oligodeoxynucleotide (ODN) directed to cell-cycle-regulatory genes after balloon angioplasty in the rat carotid injury model has been reported. The enzyme, cycline-dependent kinase (cdk) 2 kinase, plays a critical role in transition through the G1/S phase. The hemagglutination virus of Japan (HVJ) (liposome method) has been shown to increase the efficiency of cellular uptake of ODN. To test the hypothesis that inhibition of cdk2 kinase expression can inhibit ICAM-1 expression in graft arteries, we studied the effect of antisense cdk2 kinase ODN by intraluminal delivery using HVJ-liposome–mediated transfer. In this study, we demonstrate clearly that antisense cdk2 ODN treatment results in near-complete inhibition of ICAM-1 expression in neointimal formation in murine cardiac allografts.