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J Appl Physiol (May 24, 2007). doi:10.1152/japplphysiol.00100.2007
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Submitted on January 23, 2007
Accepted on May 21, 2007

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

Juliann G. Kiang1*, Phillip D. Bowman2, Xinyue Lu3, Yansong Li3, Brian W. Wu3, Horace H. Loh4, K. T. Tsen5, and George C. Tsokos6

1 Scientific Research Department, Armed Froces Radiobiology Research Institute, Bethesda, Maryland, United States; Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland, United States; Pharmacology, Uniformed Services University of the Health Sciences, Bethesda, Maryland, United States; Cellular Injury, Walter Reed Army Institute of Research, Silver Spring, Maryland, United States
2 US Army Institute of Surgical Research, Fort Sam Houston, Texas, United States
3 Cellular Injury, Walter Reed Army Institute of Research, Silver Spring, Maryland, United States
4 Pharmacology, University of Minnesota, Annapolix, Minnesota, United States
5 Physics and Astronomy, Arizona State University, Tempe, Arizona, United States
6 Rheumatology Division, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States

* To whom correspondence should be addressed. E-mail: kiangj{at}comcast.net.

Hemorrhage has been shown to increase 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. Geldananmycin, therefore, may prove useful as an adjuvant in fluids used to treat patients suffering blood loss.




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Home page
 Mol. Pharmacol.Home page
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]


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