Beneficial Effect of α-Tocopheryl Succinate in Rat Cardiac Transplants

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• 作者：Thanh K. Nguyen ; Vani Nilakantan ; Christopher C. Felix ; Ashwani K. Khanna and Galen M. Pieper
• 刊名：The Journal of Heart and Lung Transplantation
• 出版年：2006
• 出版时间：June 2006
• 年：2006
• 卷：25
• 期：6
• 页码：707-715
• 全文大小：169 K

文摘

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.