TY - JOUR
T1 - Apoptosis of cardiac myocytes during cardiac allograft rejection
T2 - Relation to induction of nitric oxide synthase
AU - Szabolcs, Matthias
AU - Michler, Robert E.
AU - Yang, Xiaochun
AU - Aji, Walif
AU - Roy, Dilip
AU - Athan, Eleni
AU - Sciacca, Robert R.
AU - Minanov, Oktavjian P.
AU - Cannon, Paul J.
PY - 1996
Y1 - 1996
N2 - Background: Apoptosis is a distinct form of programmed cell death characterized by activation of endonucleases that cleave nuclear DNA, condensation and fragmentation of nuclear chromatin, blebbing of intact membranes, and cell shrinkage and fragmentation. The mechanisms responsible are unclear, but nitric oxide (NO) generated by inducible NO synthase (iNOS) has been demonstrated to induce apoptosis in macrophages in vitro. This study investigated whether apoptosis occurs during cardiac allograft rejection and examined the relationship of apoptosis to iNOS expression. Methods and Results: Heterotopic abdominal transplantation from Lewis to Wistar-Furth rats was used as a model of cardiac allograft rejection; Lewis-to-Lewis grafts served as controls. Apoptosis was identified by DNA ladders after electrophoresis on agarose gels and by in situ labeling of DNA fragments; cell types were determined by immunohistochemistry. The number of apoptotic cardiac myocytes increased sharply from day 3 (0.31/mm2 ventricular tissue) to day 5 (l.27/mm2) after transplantation. At day 5, allografts showed a significant increase (P<.01) in apoptotic cardiac myocytes, macrophages, and endothelial cells compared with syngeneic grafts. The expression of iNOS mRNA, protein, and enzyme activity paralleled in time and extent the apoptosis of cardiac myocytes. iNOS immunostaining of infiltrating macrophages and cardiac muscle fibers increased significantly in the allografts at days 3 to 5 and was accompanied by immunostaining of both cell types for nitrotyrosine, which is indicative of peroxynitrite formation. Conclusions: Apoptosis of myocardial cells occurs during cardiac allograft rejection. Apoptosis during rejection parallels the expression of iNOS, which suggests that apoptosis may be triggered by NO and peroxynitrite.
AB - Background: Apoptosis is a distinct form of programmed cell death characterized by activation of endonucleases that cleave nuclear DNA, condensation and fragmentation of nuclear chromatin, blebbing of intact membranes, and cell shrinkage and fragmentation. The mechanisms responsible are unclear, but nitric oxide (NO) generated by inducible NO synthase (iNOS) has been demonstrated to induce apoptosis in macrophages in vitro. This study investigated whether apoptosis occurs during cardiac allograft rejection and examined the relationship of apoptosis to iNOS expression. Methods and Results: Heterotopic abdominal transplantation from Lewis to Wistar-Furth rats was used as a model of cardiac allograft rejection; Lewis-to-Lewis grafts served as controls. Apoptosis was identified by DNA ladders after electrophoresis on agarose gels and by in situ labeling of DNA fragments; cell types were determined by immunohistochemistry. The number of apoptotic cardiac myocytes increased sharply from day 3 (0.31/mm2 ventricular tissue) to day 5 (l.27/mm2) after transplantation. At day 5, allografts showed a significant increase (P<.01) in apoptotic cardiac myocytes, macrophages, and endothelial cells compared with syngeneic grafts. The expression of iNOS mRNA, protein, and enzyme activity paralleled in time and extent the apoptosis of cardiac myocytes. iNOS immunostaining of infiltrating macrophages and cardiac muscle fibers increased significantly in the allografts at days 3 to 5 and was accompanied by immunostaining of both cell types for nitrotyrosine, which is indicative of peroxynitrite formation. Conclusions: Apoptosis of myocardial cells occurs during cardiac allograft rejection. Apoptosis during rejection parallels the expression of iNOS, which suggests that apoptosis may be triggered by NO and peroxynitrite.
KW - apoptosis
KW - cells
KW - rejection
KW - transplantation
UR - http://www.scopus.com/inward/record.url?scp=0029778443&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0029778443&partnerID=8YFLogxK
U2 - 10.1161/01.CIR.94.7.1665
DO - 10.1161/01.CIR.94.7.1665
M3 - Article
C2 - 8840859
AN - SCOPUS:0029778443
SN - 0009-7322
VL - 94
SP - 1665
EP - 1673
JO - Circulation
JF - Circulation
IS - 7
ER -