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

¹Scientific Research Department, Armed Forces Radiobiology Research Institute, Bethesda; Departments of Radiation Biology, Medicine and of Pharmacology, Uniformed Services University of the Health Sciences, Bethesda; ²Department of Cellular Injury, Walter Reed Army Institute of Research, Silver Spring, Maryland; ³US Army Institute of Surgical Research, San Antonio, Texas; ⁴Department of Pharmacology, School of Medicine, University of Minnesota, Annapolis, Minnesota; ⁵Department of Physics and Astronomy, Arizona State University, Tempe, Arizona; and ⁶Rheumatology Division, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachussets

Submitted 23 January 2007 ; accepted in final form 21 May 2007

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.

hemorrhagic shock; caspase-9; cytochrome c; jejunum; lung

This article has been cited by other articles:

				J. G. Kiang, S. Krishnan, X. Lu, and Y. Li Inhibition of Inducible Nitric-Oxide Synthase Protects Human T Cells from Hypoxia-Induced Apoptosis Mol. Pharmacol., March 1, 2008; 73(3): 738 - 747. [Abstract] [Full Text] [PDF]