Upregulation of COX-2 during cardiac allograft rejection

Xiaochun Yang, Ninsheng Ma, Matthias J. Szabolcs, Jing Zhong, Eleni Athan, Robert R. Sciacca, Robert E. Michler, Gary D. Anderson, Joseph F. Wiese, Kathleen M. Leahy, Susan Gregory, Paul J. Cannon

Research output: Contribution to journalArticle

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Abstract

Background - The hypothesis that cyclooxygenase-2 (COX-2) is involved in the myocardial inflammatory response during cardiac allograft rejection was investigated using a rat heterotopic abdominal cardiac transplantation model. Methods and Results - COX-2 mRNA and protein in the myocardium of rejecting cardiac allografts were significantly elevated 3 to 5 days after transplantation compared with syngeneic controls (n=3, P<0.05). COX-2 upregulation paralleled in time and extent the upregulation of iNOS mRNA, protein, and enzyme activity in this model. COX-2 immunostaining was prominent in macrophages infiltrating the rejecting allografts and in damaged cardiac myocytes. Prostaglandin (PG) levels in rejecting allografts were also higher than in native hearts. Because NO has been reported to modulate PG synthesis by COX-2, additional transplants were performed using animals treated with a selective COX-2 inhibitor (SC-58125) and a selective inhibitor of the inducible nitric oxide synthase (iNOS) N-aminomethyl-L-lysine. At posttransplant day 5, inhibitor administration resulted in a significant reduction of COX-2 mRNA expression (3764±337 versus 5110±141 arbitrary units, n=3, P<0.05) and iNOS enzymatic activity (1.7±0.4 versus 22.8±14.4 nmol/mg protein, n=3, P<0.01) compared with vehicle-treated allogeneic transplants. Allograft survival in treated animals was increased modestly from 5.4 to 6.4 days (P<0.05). However, apoptosis of cardiac myocytes (TUNNEL method) was only marginally reduced relative to vehicle controls in treated graft recipients. The intensity of allograft rejection was also similar in the treated and untreated allografts. Conclusions - The data indicates that COX-2 expression is enhanced in parallel with iNOS in the myocardium during cardiac allograft rejection.

Original languageEnglish (US)
Pages (from-to)430-438
Number of pages9
JournalCirculation
Volume101
Issue number4
StatePublished - Feb 1 2000
Externally publishedYes

Fingerprint

Cyclooxygenase 2
Allografts
Up-Regulation
Nitric Oxide Synthase Type II
Transplants
Cardiac Myocytes
Messenger RNA
Myocardium
Proteins
Cyclooxygenase 2 Inhibitors
Heart Transplantation
Prostaglandin-Endoperoxide Synthases
Lysine
Prostaglandins
Transplantation
Macrophages
Apoptosis
Enzymes

Keywords

  • Nitric oxide
  • Prostaglandins
  • Rejection

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Yang, X., Ma, N., Szabolcs, M. J., Zhong, J., Athan, E., Sciacca, R. R., ... Cannon, P. J. (2000). Upregulation of COX-2 during cardiac allograft rejection. Circulation, 101(4), 430-438.

Upregulation of COX-2 during cardiac allograft rejection. / Yang, Xiaochun; Ma, Ninsheng; Szabolcs, Matthias J.; Zhong, Jing; Athan, Eleni; Sciacca, Robert R.; Michler, Robert E.; Anderson, Gary D.; Wiese, Joseph F.; Leahy, Kathleen M.; Gregory, Susan; Cannon, Paul J.

In: Circulation, Vol. 101, No. 4, 01.02.2000, p. 430-438.

Research output: Contribution to journalArticle

Yang, X, Ma, N, Szabolcs, MJ, Zhong, J, Athan, E, Sciacca, RR, Michler, RE, Anderson, GD, Wiese, JF, Leahy, KM, Gregory, S & Cannon, PJ 2000, 'Upregulation of COX-2 during cardiac allograft rejection', Circulation, vol. 101, no. 4, pp. 430-438.
Yang X, Ma N, Szabolcs MJ, Zhong J, Athan E, Sciacca RR et al. Upregulation of COX-2 during cardiac allograft rejection. Circulation. 2000 Feb 1;101(4):430-438.
Yang, Xiaochun ; Ma, Ninsheng ; Szabolcs, Matthias J. ; Zhong, Jing ; Athan, Eleni ; Sciacca, Robert R. ; Michler, Robert E. ; Anderson, Gary D. ; Wiese, Joseph F. ; Leahy, Kathleen M. ; Gregory, Susan ; Cannon, Paul J. / Upregulation of COX-2 during cardiac allograft rejection. In: Circulation. 2000 ; Vol. 101, No. 4. pp. 430-438.
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abstract = "Background - The hypothesis that cyclooxygenase-2 (COX-2) is involved in the myocardial inflammatory response during cardiac allograft rejection was investigated using a rat heterotopic abdominal cardiac transplantation model. Methods and Results - COX-2 mRNA and protein in the myocardium of rejecting cardiac allografts were significantly elevated 3 to 5 days after transplantation compared with syngeneic controls (n=3, P<0.05). COX-2 upregulation paralleled in time and extent the upregulation of iNOS mRNA, protein, and enzyme activity in this model. COX-2 immunostaining was prominent in macrophages infiltrating the rejecting allografts and in damaged cardiac myocytes. Prostaglandin (PG) levels in rejecting allografts were also higher than in native hearts. Because NO has been reported to modulate PG synthesis by COX-2, additional transplants were performed using animals treated with a selective COX-2 inhibitor (SC-58125) and a selective inhibitor of the inducible nitric oxide synthase (iNOS) N-aminomethyl-L-lysine. At posttransplant day 5, inhibitor administration resulted in a significant reduction of COX-2 mRNA expression (3764±337 versus 5110±141 arbitrary units, n=3, P<0.05) and iNOS enzymatic activity (1.7±0.4 versus 22.8±14.4 nmol/mg protein, n=3, P<0.01) compared with vehicle-treated allogeneic transplants. Allograft survival in treated animals was increased modestly from 5.4 to 6.4 days (P<0.05). However, apoptosis of cardiac myocytes (TUNNEL method) was only marginally reduced relative to vehicle controls in treated graft recipients. The intensity of allograft rejection was also similar in the treated and untreated allografts. Conclusions - The data indicates that COX-2 expression is enhanced in parallel with iNOS in the myocardium during cardiac allograft rejection.",
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AU - Yang, Xiaochun

AU - Ma, Ninsheng

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AU - Zhong, Jing

AU - Athan, Eleni

AU - Sciacca, Robert R.

AU - Michler, Robert E.

AU - Anderson, Gary D.

AU - Wiese, Joseph F.

AU - Leahy, Kathleen M.

AU - Gregory, Susan

AU - Cannon, Paul J.

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N2 - Background - The hypothesis that cyclooxygenase-2 (COX-2) is involved in the myocardial inflammatory response during cardiac allograft rejection was investigated using a rat heterotopic abdominal cardiac transplantation model. Methods and Results - COX-2 mRNA and protein in the myocardium of rejecting cardiac allografts were significantly elevated 3 to 5 days after transplantation compared with syngeneic controls (n=3, P<0.05). COX-2 upregulation paralleled in time and extent the upregulation of iNOS mRNA, protein, and enzyme activity in this model. COX-2 immunostaining was prominent in macrophages infiltrating the rejecting allografts and in damaged cardiac myocytes. Prostaglandin (PG) levels in rejecting allografts were also higher than in native hearts. Because NO has been reported to modulate PG synthesis by COX-2, additional transplants were performed using animals treated with a selective COX-2 inhibitor (SC-58125) and a selective inhibitor of the inducible nitric oxide synthase (iNOS) N-aminomethyl-L-lysine. At posttransplant day 5, inhibitor administration resulted in a significant reduction of COX-2 mRNA expression (3764±337 versus 5110±141 arbitrary units, n=3, P<0.05) and iNOS enzymatic activity (1.7±0.4 versus 22.8±14.4 nmol/mg protein, n=3, P<0.01) compared with vehicle-treated allogeneic transplants. Allograft survival in treated animals was increased modestly from 5.4 to 6.4 days (P<0.05). However, apoptosis of cardiac myocytes (TUNNEL method) was only marginally reduced relative to vehicle controls in treated graft recipients. The intensity of allograft rejection was also similar in the treated and untreated allografts. Conclusions - The data indicates that COX-2 expression is enhanced in parallel with iNOS in the myocardium during cardiac allograft rejection.

AB - Background - The hypothesis that cyclooxygenase-2 (COX-2) is involved in the myocardial inflammatory response during cardiac allograft rejection was investigated using a rat heterotopic abdominal cardiac transplantation model. Methods and Results - COX-2 mRNA and protein in the myocardium of rejecting cardiac allografts were significantly elevated 3 to 5 days after transplantation compared with syngeneic controls (n=3, P<0.05). COX-2 upregulation paralleled in time and extent the upregulation of iNOS mRNA, protein, and enzyme activity in this model. COX-2 immunostaining was prominent in macrophages infiltrating the rejecting allografts and in damaged cardiac myocytes. Prostaglandin (PG) levels in rejecting allografts were also higher than in native hearts. Because NO has been reported to modulate PG synthesis by COX-2, additional transplants were performed using animals treated with a selective COX-2 inhibitor (SC-58125) and a selective inhibitor of the inducible nitric oxide synthase (iNOS) N-aminomethyl-L-lysine. At posttransplant day 5, inhibitor administration resulted in a significant reduction of COX-2 mRNA expression (3764±337 versus 5110±141 arbitrary units, n=3, P<0.05) and iNOS enzymatic activity (1.7±0.4 versus 22.8±14.4 nmol/mg protein, n=3, P<0.01) compared with vehicle-treated allogeneic transplants. Allograft survival in treated animals was increased modestly from 5.4 to 6.4 days (P<0.05). However, apoptosis of cardiac myocytes (TUNNEL method) was only marginally reduced relative to vehicle controls in treated graft recipients. The intensity of allograft rejection was also similar in the treated and untreated allografts. Conclusions - The data indicates that COX-2 expression is enhanced in parallel with iNOS in the myocardium during cardiac allograft rejection.

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