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Reactive oxygen and reactive nitrogen as signaling molecules for caspase 3 activation in acute cardiac transplant rejection. Antioxid Redox Signal 2008 Jun;10(6):1031-40

Date

03/11/2008

Pubmed ID

18327972

Pubmed Central ID

PMC2424137

DOI

10.1089/ars.2007.1867

Scopus ID

2-s2.0-41349111277   16 Citations

Abstract

Apoptosis is a significant factor in cardiac dysfunction and graft failure in cardiac rejection. In this study, we examined potential signaling molecules responsible for caspase 3 activation in a model of acute cardiac allograft rejection. The roles of reactive oxygen species (ROS) and nitric oxide (NO) were determined in untreated allografts and allograft recipients treated with either cyclosporine (CsA), alpha-phenyl-t-butylnitrone (PBN, a spin-trapping agent), vitamin C (VitC), Mn(III)tetrakis (1-methyl-4-pyridyl)porphyrin); MnTmPyP, a superoxide dismutase (SOD) mimetic), or L-(1-iminoethyl)lysine) (L-NIL), an inhibitor of inducible NO synthase (iNOS) enzyme activity. Graft tissue was taken for measuring superoxide radical production, Western blotting, and direct measurement of caspase 3 activity. Activation of caspase 3 in untreated allografts was revealed by the appearance of cleaved caspase 3 from pro-caspase 3 by Western blotting and functional caspase 3 catalytic activity. CsA or PBN inhibited iNOS expression and caspase 3 activity. VitC and MnTmPyP did not alter iNOS expression or decrease NO levels but did inhibit caspase 3 activity. In contrast, L-NIL completely inhibited the increase in NO production without altering iNOS expression and inhibited caspase 3 activity. The prevention of TUNEL staining by MnTmPyP and L-NIL confirmed downstream effects of superoxide and NO on apoptosis. These studies indicate that both superoxide and NO (precursors of peroxynitrite formation) play a significant role in caspase 3 activation in cardiac allograft rejection.

Author List

Pieper GM, Nilakantan V, Nguyen TK, Hilton G, Roza AM, Johnson CP

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
Apoptosis
Caspase 3
Enzyme Activation
Graft Rejection
Heart Transplantation
Nitric Oxide Synthase Type II
Rats
Rats, Inbred Lew
Rats, Inbred WF
Reactive Nitrogen Species
Reactive Oxygen Species
Signal Transduction
jenkins-FCD Prod-478 d1509cf07a111124a2d122fd3df854cc0b993c00