INDUCIBLE NITRIC-OXIDE SYNTHASE SUPPRESSES THE DEVELOPMENT OF ALLOGRAFT ARTERIOSCLEROSIS

In cardiac transplantation, chronic rejection takes the form of an occ lusive vasculopathy. The mechanism underlying this disorder remains un clear. The purpose of this study was to investigate the role nitric ox ide (NO) may play in the development of allograft arteriosclerosis. Ra t aortic allografts from ACI donors to Wistar Furth recipients with a strong genetic disparity in both major and minor histocompatibility an tigens were used for transplantation. Allografts collected at 28 d wer e found to have significant increases in both inducible NO synthase (i NOS) mRNA and protein as well as in intimal thickness when compared wi th isografts. Inhibiting NO production with an iNOS inhibitor increase d the intimal thickening by 57.2%, indicating that NO suppresses the d evelopment of allograft arteriosclerosis. Next, we evaluated the effec t of cyclosporine (CsA) on iNOS expression and allograft arteriosclero sis. CsA (10 mg/kg/d) suppressed the expression of iNOS in response to balloon-induced aortic injury. Similarly, CsA inhibited iNOS expressi on in the aortic allografts, associated with a 65% increase in intimal thickening, Finally, we investigated the effect of adenoviral-mediate d iNOS gene transfer on allograft arteriosclerosis. Transduction with iNOS using an adenoviral vector suppressed completely the development of allograft arteriosclerosis in both untreated recipients and recipie nts treated with CsA. These results suggest that the early immune-medi ated upregulation in iNOS expression partially protects aortic allogra fts from the development of allograft arteriosclerosis, and that iNOS gene transfer strategies may prove useful in preventing the developmen t of this otherwise untreatable disease process.