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This Article Full Text Free Full Text (PDF) Free All Versions of this Article: 102/3/933    most recent 00919.2006v1 Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (2) Citing Articles via Google Scholar Google Scholar Articles by Kiang, J. G. Articles by Tsokos, G. C. Search for Related Content PubMed PubMed Citation Articles by Kiang, J. G. Articles by Tsokos, G. C.

Androstenediol inhibits the trauma-hemorrhage-induced increase in caspase-3 by downregulating the inducible nitric oxide synthase pathway

¹Department of Cellular Injury, Walter Reed Army Institute of Research, Silver Spring, Maryland; ²Armed Forces Radiobiology Research Institute and Departments of ³Medicine and ⁴Pharmacology, Uniformed Services University of the Health Sciences, Bethesda, Maryland; and ⁵Center for Surgical Research and Department of Surgery, University of Alabama, Birmingham, Alabama

Submitted 21 August 2006 ; accepted in final form 8 November 2006

Soft tissue trauma and hemorrhage (T-H) diminishes various aspects of liver function, while it increases hepatic nitrate/nitrite, inducible nitric oxide synthase (iNOS), and endothelin-1 levels. Treatment with androstenediol (AED) inhibits the T-H-induced alterations of the above parameters. We sought to identify the molecular events underlying the beneficial effect of AED. Exposure of rats to T-H significantly increased the caspase-3 activity and protein, whereas treatment with AED significantly limited these increases. AED treatment also suppressed the T-H-induced increase in iNOS by effectively altering the levels of key transcription factors involved in the regulation of iNOS expression. Immunoprecipitation and immunoblotting analyses indicate that T-H increased apoptosome formation, and AED treatment significantly decreased it. Modulating the iNOS protein by transfecting cells with iNOS gene or small interfering RNA further confirmed the correlation between iNOS and caspase-3. Our data indicate that AED limits caspase-3 expression by suppressing the expression of transcription factors involved in the production of iNOS, resulting in decreased apoptosome. AED can potentially be a useful adjuvant for limiting liver apoptosis following T-H shock.

hemorrhage shock; caspase-9; cytochrome c; adiol; 5-androstene-3, 17-diol

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