Human Cytomegalovirus Immediate-Early Protein IE2–86, but not IE1–72, Causes Graft Coronary Arteriopathy in the Transplanted Rat Heart

Background 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. Methods and Results 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. Conclusions 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.