Kiang Juliann G, Bowman Phillip D, Lu Xinyue, Li Yansong, Wu Brian W, Loh Horace H, Tsen K T, Tsokos George C
Scientific Research Department, Armed Forces Radiobiology Research Institute, BLDG 46, Rm. 2423, Uniformed Services University of the Health Sciences, 8901 Wisconsin Ave., Bethesda, MD 20889-5603, USA.
J Appl Physiol (1985). 2007 Sep;103(3):1045-55. doi: 10.1152/japplphysiol.00100.2007. Epub 2007 May 24.
Hemorrhage has been shown to increase inducible nitric oxide synthase (iNOS) and deplete ATP levels in tissues and geldanamycin limits both processes. Moreover, it is evident that inhibition of iNOS reduces caspase-3 and increases survival. Thus we sought to identify the molecular events responsible for the beneficial effect of geldanamycin. Hemorrhage in mice significantly increased caspase-3 activity and protein while treatment with geldanamycin significantly limited these increases. Similarly, geldanamycin inhibited increases in proteins forming the apoptosome (a complex of caspase-9, cytochrome c, and Apaf-1). Modulation of the expression of iNOS by iNOS gene transfection or siRNA treatment demonstrated that the level of iNOS correlates with caspase-3 activity. Our data indicate that geldanamycin limits caspase-3 expression and protects from organ injury by suppressing iNOS expression and apoptosome formation. Geldanamycin, therefore, may prove useful as an adjuvant in fluids used to treat patients suffering blood loss.
出血已被证明会增加诱导型一氧化氮合酶（iNOS）的表达，并耗尽组织中的ATP水平，而格尔德霉素可限制这两个过程。此外，很明显抑制iNOS可降低半胱天冬酶-3的水平并提高生存率。因此，我们试图确定导致格尔德霉素产生有益作用的分子事件。小鼠出血显著增加了半胱天冬酶-3的活性和蛋白水平，而用格尔德霉素治疗则显著限制了这些增加。同样，格尔德霉素抑制了形成凋亡小体（半胱天冬酶-9、细胞色素c和凋亡蛋白酶激活因子-1的复合物）的蛋白增加。通过iNOS基因转染或siRNA处理调节iNOS的表达表明，iNOS的水平与半胱天冬酶-3的活性相关。我们的数据表明，格尔德霉素通过抑制iNOS表达和凋亡小体形成来限制半胱天冬酶-3的表达并保护器官免受损伤。因此，格尔德霉素可能被证明是治疗失血患者所用液体中的一种有用佐剂。
