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J Thorac Cardiovasc Surg 2006;131:898-906
© 2006 The American Association for Thoracic Surgery

Cardiothoracic Transplantation

Antagonizing reactive oxygen by treatment with a manganese (III) metalloporphyrin–based superoxide dismutase mimetic in cardiac transplants

Vani Nilakantan, PhD a , Xianghua Zhou, MD a , Gail Hilton, MS a , Yang Shi, PhD b , John E. Baker, PhD b , Ashwani K. Khanna, PhD c , Galen M. Pieper, PhD a , d , *

a Department of Surgery, Divisions of Transplant Surgery, Medical College of Wisconsin, Milwaukee, Wis
b Pediatric Surgery, Medical College of Wisconsin, Milwaukee, Wis
c Department of Medicine, Medical College of Wisconsin, Milwaukee, Wis
d Free Radical Research Center, Medical College of Wisconsin, Milwaukee, Wis

Received for publication July 28, 2005; revisions received October 14, 2005; accepted for publication November 8, 2005.

* Address for reprints: Galen M. Pieper, PhD, Transplant Surgery, Medical College of Wisconsin, 9200 West Wisconsin Ave, Milwaukee, WI 53226 (Email: gmpieper{at}mcw.edu).

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.

Abbreviations and Acronyms FasL = Fas ligand; IFN-{gamma} = interferon {gamma}; IL = interleukin; iNOS = inducible nitric oxide synthase; MnSOD = manganese superoxide dismutase; MnTBAP = Manganese (III) tetrakis(4-benzoic acid) porphyrin chloride; MnTmPyP = Manganese (III) tetrakis(1-methyl-4-pyridyl) porphyrin pentachloride; NO = nitric oxide; POD = postoperative day; RT-PCR = reverse transcriptase polymerase chain reaction; SOD = superoxide dismutase; TNF-{alpha} = tumor necrosis factor {alpha}




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