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.