Inducible nitric oxide synthase suppresses the development of allograft arteriosclerosis

Larry L. Shears, Nobuyoshi Kawaharada, Edith Tzeng, Timothy R. Billiar, Simon C. Watkins, Imre Kovesdi, Alena Lizonova, Si M. Pham*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

221 Scopus citations


In cardiac transplantation, chronic rejection takes the form of an occlusive vasculopathy. The mechanism underlying this disorder remains unclear. The purpose of this study was to investigate the role nitric oxide (NO) may play in the development of allograft arteriosclerosis. Rat aortic allografts from ACI donors to Wistar Furth recipients with a strong genetic disparity in both major and minor histocompatibility antigens were used for transplantation. Allografts collected at 28 d were found to have significant increases in both inducible NO synthase (iNOS) mRNA and protein as well as in intimal thickness when compared with isografts. Inhibiting NO production with an iNOS inhibitor increased the intimal thickening by 57.2%, indicating that NO suppresses the development of allograft arteriosclerosis. Next, we evaluated the effect of cyclosporine (CsA) on iNOS expression and allograft arteriosclerosis. CsA (10 mg/kg/d) suppressed the expression of iNOS in response to balloon-induced aortic injury. Similarly, CsA inhibited iNOS expression in the aortic allografts, associated with a 65% increase in intimal thickening. Finally, we investigated the effect of adenoviral- mediated 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 recipients treated with CsA. These results suggest that the early immune-mediated upregulation in iNOS expression partially protects aortic allografts from the development of allograft arteriosclerosis, and that iNOS gene transfer strategies may prove useful in preventing the development of this otherwise untreatable disease process.

Original languageEnglish
Pages (from-to)2035-2042
Number of pages8
JournalJournal of Clinical Investigation
Issue number8
StatePublished - 15 Oct 1997
Externally publishedYes


  • Chronic rejection
  • Cyclosporine
  • Gene therapy
  • Intimal hyperplasia
  • Transplantation


Dive into the research topics of 'Inducible nitric oxide synthase suppresses the development of allograft arteriosclerosis'. Together they form a unique fingerprint.

Cite this