Beneficial effect of alpha-tocopheryl succinate in rat cardiac transplants.
BACKGROUND
Anti-oxidant vitamins have increasingly been used to supplement traditional post-surgical treatment in cardiac transplant recipients. However, the mechanism(s) of action have not been determined. In this study we examined the effects of a novel vitamin E analog, alpha-tocopheryl polyethylene glycol-100 succinate (alpha-TPGS), and low-dose cyclosporine (CsA) in the treatment of acute and delayed cardiac rejection.


METHODS
In situ sonomicrometry, histologic rejection and graft survival were determined in untreated rat cardiac allograft recipients and recipients receiving CsA, alpha-TPGS or CsA plus alpha-TPGS. DNA binding of nuclear factor (NF)-kappaB and AP-1, inducible nitric oxide synthase (iNOS) protein, caspase-3 activity and lymphocyte proliferation were determined.


RESULTS
alpha-TPGS significantly (p < 0.05) prolonged graft survival equipotent to low-dose CsA. Treatment with CsA plus alpha-TPGS further enhanced graft survival (p < 0.001). CsA or alpha-TPGS alone decreased rejection, with the greatest decrease seen using combination therapy. Graft fractional shortening was improved by CsA or alpha-TPGS alone (p < 0.01), whereas distention in systolic and diastolic lengths in untreated allografts was prevented by CsA, alpha-TPGS and combination therapy. Nitrosylation of heme protein was inhibited by alpha-TPGS and abolished by CsA or CsA plus alpha-TPGS. Expression of iNOS was decreased 50% by alpha-TPGS equipotent to CsA, but apparently via an NF-kappaB- and AP-1-independent pathway. Caspase-3 activity, an index of apoptosis, was increased only in untreated allografts. In addition, alpha-TPGS markedly inhibited mitogen-stimulated proliferation by both rat and human lymphocytes.


CONCLUSIONS
alpha-TPGS has a significant effect in limiting lymphocyte proliferation and activation. This might explain the equipotent action of alpha-TPGS vs low-dose CsA and its action to potentiate graft survival and limit graft rejection and dysfunction.
Nguyen
Thanh K
TK
Department of Surgery, Division of Transplant Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA.
Nilakantan
Vani
V
Felix
Christopher C
CC
Khanna
Ashwani K
AK
Pieper
Galen M
GM
D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use*; D017209:Apoptosis / Q000502:physiology; D015153:Blotting, Western; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D049109:Cell Proliferation; D004578:Electron Spin Resonance Spectroscopy; D024202:Electrophoretic Mobility Shift Assay; D006084:Graft Rejection / Q000503:physiopathology; D006085:Graft Survival / Q000187:drug effects*; D006339:Heart Rate / Q000187:drug effects; D016027:Heart Transplantation / Q000276:immunology*; D051381:Rats; D011917:Rats, Inbred Lew; D011920:Rats, Inbred WF; D024505:Tocopherols; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000627:therapeutic use
D000975:Antioxidants; D014810:Vitamin E; C505407:CASP3 protein, human; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; D024505:Tocopherols