Beneficial Effect of α-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, α-tocopheryl polyethylene glycol-100 succinate (α-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, α-TPGS or CsA plus α-TPGS. DNA binding of nuclear factor (NF)-κB and AP-1, inducible nitric oxide synthase (iNOS) protein, caspase-3 activity and lymphocyte proliferation were determined. Results: α-TPGS significantly (p < 0.05) prolonged graft survival equipotent to low-dose CsA. Treatment with CsA plus α-TPGS further enhanced graft survival (p < 0.001). CsA or α-TPGS alone decreased rejection, with the greatest decrease seen using combination therapy. Graft fractional shortening was improved by CsA or α-TPGS alone (p < 0.01), whereas distention in systolic and diastolic lengths in untreated allografts was prevented by CsA, α-TPGS and combination therapy. Nitrosylation of heme protein was inhibited by α-TPGS and abolished by CsA or CsA plus α-TPGS. Expression of iNOS was decreased 50% by α-TPGS equipotent to CsA, but apparently via an NF-κB– and AP-1–independent pathway. Caspase-3 activity, an index of apoptosis, was increased only in untreated allografts. In addition, α-TPGS markedly inhibited mitogen-stimulated proliferation by both rat and human lymphocytes. Conclusions: α-TPGS has a significant effect in limiting lymphocyte proliferation and activation. This might explain the equipotent action of α-TPGS vs low-dose CsA and its action to potentiate graft survival and limit graft rejection and dysfunction. [Copyright &y& Elsevier]