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

被引:22
作者
Kiang, Juliann G.
Peckham, Russell M.
Duke, Leah E.
Shimizu, Tomoharu
Chaudry, Irshad H.
Tsokos, George C.
机构
[1] Armed Forces Radiobiol Res Inst, Bethesda, MD 20889 USA
[2] Walter Reed Army Inst Res, Dept Cellular Injury, Silver Spring, MD USA
[3] Uniformed Serv Univ Hlth Sci, Dept Med, Bethesda, MD 20814 USA
[4] Uniformed Serv Univ Hlth Sci, Dept Pharmacol, Bethesda, MD 20814 USA
[5] Univ Alabama Birmingham, Surg Res Ctr, Birmingham, AL USA
[6] Univ Alabama Birmingham, Dept Surg, Birmingham, AL 35294 USA
关键词
hemorrhage shock; caspase-9; cytochrome c; adiol; 5-androstene-3; beta; 17; beta-diol;
D O I
10.1152/japplphysiol.00919.2006
中图分类号
Q4 [生理学];
学科分类号
071003 ;
摘要
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.
引用
收藏
页码:933 / 941
页数:9
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