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J Appl Physiol (1985). 2007 Sep;103(3):1045-55. Epub 2007 May 24.

Geldanamycin inhibits hemorrhage-induced increases in caspase-3 activity: role of inducible nitric oxide synthase.

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  • 1Scientific 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.


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.

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