Kiang Juliann G, Peckham Russell M, Duke Leah E, Shimizu Tomoharu, Chaudry Irshad H, Tsokos George C
Department of Cellular Injury, Walter Reed Army Institute of Research, Silver Spring, MD, USA.
J Appl Physiol (1985). 2007 Mar;102(3):933-41. doi: 10.1152/japplphysiol.00919.2006. Epub 2006 Nov 16.
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.
软组织创伤和出血（T-H）会削弱肝功能的各个方面，同时会增加肝脏中的硝酸盐/亚硝酸盐、诱导型一氧化氮合酶（iNOS）和内皮素-1水平。雄烯二醇（AED）治疗可抑制T-H诱导的上述参数变化。我们试图确定AED有益作用背后的分子事件。将大鼠暴露于T-H会显著增加半胱天冬酶-3的活性和蛋白水平，而AED治疗则显著限制了这些增加。AED治疗还通过有效改变参与iNOS表达调控的关键转录因子水平，抑制了T-H诱导的iNOS增加。免疫沉淀和免疫印迹分析表明，T-H增加了凋亡小体的形成，而AED治疗则显著降低了凋亡小体的形成。通过用iNOS基因或小干扰RNA转染细胞来调节iNOS蛋白，进一步证实了iNOS与半胱天冬酶-3之间的相关性。我们的数据表明，AED通过抑制参与iNOS产生的转录因子的表达来限制半胱天冬酶-3的表达，从而导致凋亡小体减少。AED有可能成为限制T-H休克后肝脏细胞凋亡的有用佐剂。
