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Protective mechanisms of a metalloporphyrinic peroxynitrite decomposition catalyst, WW85, in rat cardiac transplants. J Pharmacol Exp Ther 2005 Jul;314(1):53-60

Date

03/24/2005

Pubmed ID

15784653

DOI

10.1124/jpet.105.083493

Scopus ID

2-s2.0-23044479642   34 Citations

Abstract

Nitric oxide (NO) derived from inducible NO synthase has been implicated in cardiac rejection. However, little is known about the role of the reactive nitrogen species peroxynitrite. We examined the protective actions of a peroxynitrite decomposition catalyst, WW85, in an experimental model of acute cardiac rejection. Heterotopic, abdominal transplantation of rat donor hearts was performed. Groups included isografts, allografts, or allografts treated with WW85, cyclosporine, or cyclosporine + WW85. We determined graft survival, histological rejection, and graft function (by in situ sonomicrometry). Intragraft biochemical analysis of cytokines and proapoptotic and antiapoptotic gene expression using reverse transcriptase-polymerase chain reaction were determined. Treatment with WW85 or cyclosporine alone prolonged graft survival, improved graft function, and decreased histological rejection. Graft survival was further significantly (P < 0.001) enhanced by combination treatment. A decrease was also shown in nitrotyrosine, poly(ADP-ribose) polymerase (PARP) activation, and lipid peroxide formation by WW85 that was potentiated when given in combination with cyclosporine. Benefits could not be ascribed to changes in intragraft myeloperoxidase activity. Only combination therapy produced significant decreases in inflammatory cytokine gene expression, suggesting that WW85 acted primarily downstream of these stimuli. In general, WW85 had no direct action on expression of the proapoptotic gene, Fas ligand; however, WW85 given alone or with cyclosporine enhanced expression of antiapoptotic genes Bcl-2 and Bcl-xL. Collectively, these findings suggest a protective action of the peroxynitrite decomposition catalyst WW85 on graft rejection that is independent of any action on leukocyte sequestration and cytokine gene expression. Rather, effects seem to be downstream on decreased protein nitration, decreased lipid peroxidation, and decreased PARP activation.

Author List

Pieper GM, Nilakantan V, Chen M, Zhou J, Khanna AK, Henderson JD Jr, Johnson CP, Roza AM, Szabó C

Authors

Christopher P. Johnson MD Professor in the Surgery department at Medical College of Wisconsin
Allan M. Roza MD Professor in the Surgery department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Anti-Inflammatory Agents, Non-Steroidal
Antioxidants
Apoptosis
Catalysis
Cyclosporine
Gene Expression
Graft Rejection
Graft Survival
Heart Transplantation
Immunosuppressive Agents
Malondialdehyde
Metalloporphyrins
Myocardium
Neutrophils
Peroxidase
Peroxynitrous Acid
Poly Adenosine Diphosphate Ribose
Rats
Rats, Inbred Lew
Rats, Wistar
Tyrosine
jenkins-FCD Prod-478 d1509cf07a111124a2d122fd3df854cc0b993c00