Apoptosis and increased expression of inducible nitric oxide synthase in human allograft rejection

Matthias J. Szabolcs, Stefano Ravalli, Oktavijan Minanov, Robert R. Sciacca, Robert E. Michler, Paul J. Cannon

Research output: Contribution to journalArticle

121 Scopus citations

Abstract

Background. The mechanisms of myocyte death during cardiac allograft rejection are incompletely understood. In a previous study using a rat heterotopic cardiac allograft model, we showed that cardiac myocyte apoptosis, inducible nitric oxide synthase (iNOS) mRNA, protein and enzyme activity, and nitrotyrosine increased simultaneously during cardiac allograft rejection. This study was designed to investigate whether apoptosis and expression of iNOS occur in human cardiac allograft rejection. Methods. Right ventricular endomyocardial biopsies from 30 cases of allograft rejection (International Society of Heart and Lung Transplantation grade 3A/B) were compared with 12 biopsies with no rejection (International Society of Heart and Lung Transplantation grade 0). Samples were co-labeled for apoptosis and muscle actin. Serial sections were stained for iNOS, nitrotyrosine, and the leukocyte markers CD3, CD4, CD8, and CD68 to identify T-cell subpopulations and macrophages. Results. Biopsies with cardiac allograft rejection showed a 30-fold increase of apoptotic cells when compared with controls. Most apoptotic cardiac myocytes were found in proximity to macrophage (CD68+)- rich inflammatory infiltrates. iNOS immunoreactivity was strongest in macrophages and adjacent myocytes, which also showed high levels of nitrotyrosine, representing damage by peroxynitrite. Conclusions. Apoptosis is a major form of myocyte death during human cardiac allograft rejection. Cardiac myocyte apoptosis is closely associated with expression of iNOS in macrophages and myocytes and with nitration of myocyte proteins by peroxynitrite.

Original languageEnglish (US)
Pages (from-to)804-812
Number of pages9
JournalTransplantation
Volume65
Issue number6
DOIs
StatePublished - Mar 27 1998
Externally publishedYes

ASJC Scopus subject areas

  • Transplantation

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