Upregulation of COX-2 During Cardiac Allograft Rejection

Xiaochun Yang, Ninsheng Ma, Matthias J. Szabolcs, Jing Zhong, Eleni Athan, Robert R. Sciacca, Robert E. Michler, Gary D. Anderson, Joseph F. Wiese, Kathleen M. Leahy, Susan Gregory, Paul J. Cannon
2000 Circulation  
Background-The hypothesis that cyclooxygenase-2 (COX-2) is involved in the myocardial inflammatory response during cardiac allograft rejection was investigated using a rat heterotopic abdominal cardiac transplantation model. Methods and Results-COX-2 mRNA and protein in the myocardium of rejecting cardiac allografts were significantly elevated 3 to 5 days after transplantation compared with syngeneic controls (nϭ3, PϽ0.05). COX-2 upregulation paralleled in time and extent the upregulation of
more » ... upregulation of iNOS mRNA, protein, and enzyme activity in this model. COX-2 immunostaining was prominent in macrophages infiltrating the rejecting allografts and in damaged cardiac myocytes. Prostaglandin (PG) levels in rejecting allografts were also higher than in native hearts. Because NO has been reported to modulate PG synthesis by COX-2, additional transplants were performed using animals treated with a selective COX-2 inhibitor (SC-58125) and a selective inhibitor of the inducible nitric oxide synthase ( iNOS) N-aminomethyl-L-lysine. At posttransplant day 5, inhibitor administration resulted in a significant reduction of COX-2 mRNA expression (3764Ϯ337 versus 5110Ϯ141 arbitrary units, nϭ3, PϽ0.05) and iNOS enzymatic activity (1.7Ϯ0.4 versus 22.8Ϯ14.4 nmol/mg protein, nϭ3, PϽ0.01) compared with vehicle-treated allogeneic transplants. Allograft survival in treated animals was increased modestly from 5.4 to 6.4 days (PϽ0.05). However, apoptosis of cardiac myocytes (TUNNEL method) was only marginally reduced relative to vehicle controls in treated graft recipients. The intensity of allograft rejection was also similar in the treated and untreated allografts. Conclusions-The data indicates that COX-2 expression is enhanced in parallel with iNOS in the myocardium during cardiac allograft rejection. (Circulation. 2000;101:430-438.)
doi:10.1161/01.cir.101.4.430 pmid:10653836 fatcat:gm4odw3uyzgczi6yp5ueiwb3h4