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

Juliann G. Kiang, Phillip D. Bowman, Xinyue Lu, Yansong Li, Brian W. Wu, Horace H. Loh, Kong-Thon Tsen, George C. Tsokos

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1045-1055
Number of pages11
JournalJournal of Applied Physiology
Volume103
Issue number3
DOIs
StatePublished - Sep 2007

Fingerprint

Nitric Oxide Synthase Type II
Caspase 3
Hemorrhage
Apoptosomes
Cytochromes c1
Caspase 9
Small Interfering RNA
Transfection
geldanamycin
Proteins
Adenosine Triphosphate
Survival
Wounds and Injuries
Therapeutics
Genes

Keywords

  • Caspase-9
  • Cytochrome c
  • Hemorrhagic shock
  • Jejunum
  • Lung

ASJC Scopus subject areas

  • Physiology
  • Endocrinology
  • Orthopedics and Sports Medicine
  • Physical Therapy, Sports Therapy and Rehabilitation

Cite this

Geldanamycin inhibits hemorrhage-induced increases in caspase-3 activity : Role of inducible nitric oxide synthase. / Kiang, Juliann G.; Bowman, Phillip D.; Lu, Xinyue; Li, Yansong; Wu, Brian W.; Loh, Horace H.; Tsen, Kong-Thon; Tsokos, George C.

In: Journal of Applied Physiology, Vol. 103, No. 3, 09.2007, p. 1045-1055.

Research output: Contribution to journalArticle

Kiang, Juliann G. ; Bowman, Phillip D. ; Lu, Xinyue ; Li, Yansong ; Wu, Brian W. ; Loh, Horace H. ; Tsen, Kong-Thon ; Tsokos, George C. / Geldanamycin inhibits hemorrhage-induced increases in caspase-3 activity : Role of inducible nitric oxide synthase. In: Journal of Applied Physiology. 2007 ; Vol. 103, No. 3. pp. 1045-1055.
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