Induction of myocardial nitric oxide synthase by cardiac allograft rejection

Xiaochun Yang, Nepal Chowdhury, Bolin Cai, Jerold Brett, Charles Marboe, Robert R. Sciacca, Robert E. Michler, Paul J. Cannon

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190 Scopus citations

Abstract

Cardiac transplantation, effective therapy for end-stage heart failure, is frequently complicated by allograft rejection, the mechanisms of which remain incompletely understood. Nitric oxide (NO), a vasodilator which is cytotoxic and negatively inotropic, can be produced in large amounts by an inducible NO synthase (iNOS) in response to cytokines. To investigate whether iNOS is induced during cardiac allograft rejection, hearts from Lewis or Wistar- Furth rats were transplanted into Lewis recipients. At day 5, allogeneic grafts manifested reduced contractility and histologic evidence of rejection (inflammatory infiltrate, edema, necrosis of myocytes). The mRNA for iNOS and iNOS protein were detected in ventricular homogenates and in isolated cardiac myocytes from rejecting allogeneic grafts but not in tissue and myocytes from syngeneic control grafts. Immunocytochemistry showed increased iNOS staining in infiltrating macrophages and in microvascular endothelial cells and cardiac muscle fibers and also in isolated purified cardiac myocytes from the rejecting allografts. Using a myocardial cytosolic iNOS preparation, nitrite formation from L-arginine and [3H]citrulline formation from [3H]L-arginine were increased significantly in the rejecting allogeneic grafts (P < 0.01). Myocardial cyclic GMP was also increased significantly (P < 0.05). The data indicate myocardial iNOS mRNA, protein and enzyme activity are induced in infiltrating macrophages and cardiac myocytes of the rejecting allogeneic grafts. Synthesis of NO by iNOS may contribute to myocyte necrosis and ventricular failure during cardiac allograft rejection.

Original languageEnglish (US)
Pages (from-to)714-721
Number of pages8
JournalJournal of Clinical Investigation
Volume94
Issue number2
DOIs
StatePublished - Aug 1994
Externally publishedYes

Keywords

  • allograft rejection
  • heart transplantation
  • inducible NO synthase

ASJC Scopus subject areas

  • Medicine(all)

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    Yang, X., Chowdhury, N., Cai, B., Brett, J., Marboe, C., Sciacca, R. R., Michler, R. E., & Cannon, P. J. (1994). Induction of myocardial nitric oxide synthase by cardiac allograft rejection. Journal of Clinical Investigation, 94(2), 714-721. https://doi.org/10.1172/JCI117390