Apoptosis of cardiac myocytes during cardiac allograft rejection

Relation to induction of nitric oxide synthase

Matthias Szabolcs, Robert E. Michler, Xiaochun Yang, Walif Aji, Dilip Roy, Eleni Athan, Robert R. Sciacca, Oktavjian P. Minanov, Paul J. Cannon

Research output: Contribution to journalArticle

177 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1665-1673
Number of pages9
JournalCirculation
Volume94
Issue number7
StatePublished - 1996
Externally publishedYes

Fingerprint

Cardiac Myocytes
Nitric Oxide Synthase
Allografts
Apoptosis
Peroxynitrous Acid
Macrophages
Nitric Oxide
Inbred WF Rats
Heterotopic Transplantation
Transplants
Agar Gel Electrophoresis
Endonucleases
DNA
Nitric Oxide Synthase Type II
DNA Fragmentation
Blister
Chromatin
Myocardium
Cell Death
Endothelial Cells

Keywords

  • apoptosis
  • cells
  • rejection
  • transplantation

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Szabolcs, M., Michler, R. E., Yang, X., Aji, W., Roy, D., Athan, E., ... Cannon, P. J. (1996). Apoptosis of cardiac myocytes during cardiac allograft rejection: Relation to induction of nitric oxide synthase. Circulation, 94(7), 1665-1673.

Apoptosis of cardiac myocytes during cardiac allograft rejection : Relation to induction of nitric oxide synthase. / Szabolcs, Matthias; Michler, Robert E.; Yang, Xiaochun; Aji, Walif; Roy, Dilip; Athan, Eleni; Sciacca, Robert R.; Minanov, Oktavjian P.; Cannon, Paul J.

In: Circulation, Vol. 94, No. 7, 1996, p. 1665-1673.

Research output: Contribution to journalArticle

Szabolcs, M, Michler, RE, Yang, X, Aji, W, Roy, D, Athan, E, Sciacca, RR, Minanov, OP & Cannon, PJ 1996, 'Apoptosis of cardiac myocytes during cardiac allograft rejection: Relation to induction of nitric oxide synthase', Circulation, vol. 94, no. 7, pp. 1665-1673.
Szabolcs, Matthias ; Michler, Robert E. ; Yang, Xiaochun ; Aji, Walif ; Roy, Dilip ; Athan, Eleni ; Sciacca, Robert R. ; Minanov, Oktavjian P. ; Cannon, Paul J. / Apoptosis of cardiac myocytes during cardiac allograft rejection : Relation to induction of nitric oxide synthase. In: Circulation. 1996 ; Vol. 94, No. 7. pp. 1665-1673.
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abstract = "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.",
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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.

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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.

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