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.


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.
D000818:Animals; D003331:Coronary Vessels / Q000473:pathology*; D003586:Cytomegalovirus Infections / Q000150:complications; D006084:Graft Rejection / Q000473:pathology / Q000821:virology*; D016027:Heart Transplantation / Q000401:mortality; D006801:Humans; D006965:Hyperplasia / Q000821:virology; D017874:Immediate-Early Proteins / Q000235:genetics* / Q000378:metabolism; D007700:Kinetics; D008297:Male; D008562:Membrane Glycoproteins; D051381:Rats; D011917:Rats, Inbred Lew; D015534:Trans-Activators; D014162:Transfection; D014759:Viral Envelope Proteins; D014764:Viral Proteins; D001616:beta-Galactosidase / Q000032:analysis / Q000235:genetics
C088645:IE1 protein, cytomegalovirus; C069186:IE2 protein, Cytomegalovirus; D017874:Immediate-Early Proteins; D008562:Membrane Glycoproteins; D015534:Trans-Activators; C077406:UL115 protein, Human herpesvirus 5; D014759:Viral Envelope Proteins; D014764:Viral Proteins; C071440:glycoprotein H, Cytomegalovirus; C499358:glycoprotein H, Human cytomegalovirus; C439068:glycoprotein O, cytomegalovirus; D001616:beta-Galactosidase