Human cytomegalovirus immediate-early protein IE2-86, but not IE1-72, causes graft coronary arteriopathy in the transplanted rat heart.

Abstract

Graft coronary arteriopathy (GCA) after heart transplantation is a major factor limiting the long-term survival of the recipients. Human cytomegalovirus (HCMV) infection is a possible cause of this disease which is characterized by diffuse intimal thickening resulting from smooth muscle cell migration and proliferation. It has been reported that HCMV immediate-early (IE) proteins, IE1 and IE2, could play an important role in the development of this disease; however, the precise in vivo role of these proteins in causing GCA has not been clarified. Excised Lewis rat hearts were transfected with HCMV IE1-72, IE2-86 or control plasmid by intra-coronary infusion of Hemagglutinating Virus of Japan-liposome, and transplanted into syngeneic recipients' abdomens. All cardiac grafts continued to beat well throughout the incubation period in the absence of immunosuppression. Exclusive expression of IE1-72 or IE2-86 protein in coronary artery walls was demonstrated after IE1-72 or IE2-86 gene transfection, respectively. Luminal occlusion as a consequence of intimal thickening of graft coronary arteries developed in the IE2-86 transfected hearts at day 21 after transplantation (30.1+/-3.4% occlusion, P<0.0001), compared with the IE1-72 and control transfected ones (8.2+/-1.6 and 6.8+/-1.1%, respectively). In contrast, there was no significant difference in luminal occlusion between the IE1-72 and control transfected hearts. We have demonstrated that expression of IE2-86 alone, but not IE1-72, causes intimal hyperplasia after cardiac transplantation. IE2-86 protein may therefore prove to be a useful target in therapies aimed at preventing HCMV-related GCA and improving the long-term result of cardiac transplantation.