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Antagonizing reactive oxygen by treatment with a manganese (III) metalloporphyrin-based superoxide dismutase mimetic in cardiac transplants. J Thorac Cardiovasc Surg 2006 Apr;131(4):898-906

Date

04/04/2006

Pubmed ID

16580450

DOI

10.1016/j.jtcvs.2005.11.015

Scopus ID

2-s2.0-33645389954   17 Citations

Abstract

OBJECTIVE: Oxidative stress might be an important factor contributing to injury during alloimmune activation. Herein, we evaluated the efficacy of a superoxide dismutase mimetic, manganese (III) tetrakis (1-methyl-4-pyridyl) porphyrin pentachloride (MnTmPyP), on cytokine gene expression and apoptotic signaling in a rat model of cardiac transplantation.

METHODS: Lewis-->Lewis (isografts) or Wistar-Furth-->Lewis (allografts) heterotopic rat transplants without and with treatment with MnTmPyP were used. Reactive oxygen formation was determined on the basis of dihydroethidine fluorescence and lucigenin-enhanced chemiluminescence. In situ graft function was determined by means of sonomicrometry. Inflammatory cytokine, proapoptotic, and antiapoptotic gene expression at either postoperative day 4 (early rejection) or postoperative day 6 (late rejection) was determined by means of reverse transcriptase polymerase chain reaction.

RESULTS: An increased production of reactive oxygen in allografts was inhibited to isograft control levels by MnTmPyP. MnTmPyP restored either the percentage of fractional shortening, the distended diastolic and systolic myocardial segment lengths, or both in allografts. Of the increases in cytokine and proapoptotic gene expression in allografts, only interleukin 6 was decreased by MnTmPyP. MnTmPyP inhibited antiapoptotic gene expression (Bcl-2 and Bcl-xL) during early rejection but restored expression at later stages. The increase in activated caspase-3 levels in allografts was inhibited by MnTmPyP.

CONCLUSIONS: The mechanism of the beneficial effect of MnTmPyP on graft function appear related, in part, to scavenging O2*- and by decreasing apoptotic signaling rather than an effect on inflammatory cytokine gene expression.

Author List

Nilakantan V, Zhou X, Hilton G, Shi Y, Baker JE, Khanna AK, Pieper GM

Author

John E. Baker PhD Professor in the Surgery department at Medical College of Wisconsin




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

Animals
Apoptosis
Caspase 3
Caspases
Cytokines
Heart Transplantation
Luminescence
Metalloporphyrins
Models, Animal
Oxidative Stress
Rats
Rats, Inbred Lew
Rats, Inbred WF
Reactive Oxygen Species
Reverse Transcriptase Polymerase Chain Reaction
jenkins-FCD Prod-482 91ad8a360b6da540234915ea01ff80e38bfdb40a