Geldanamycin treatment inhibits hemorrhage-induced increases in KLF6 and iNOS expression in unresuscitated mouse organs: role of inducible HSP70.
The aim of this study was to determine whether hemorrhage affects the levels of a variety of stress-related proteins and whether changes can be inhibited by drugs reported to provide protection from ischemia and reperfusion injury. Male Swiss Webster mice were subjected to a 40% hemorrhage without resuscitation. Western blot analysis indicated that c-Jun (an AP-1 protein), Kruppel-like factor 6 (KFL6), and inducible nitric oxide synthase (iNOS) were upregulated sequentially in that order. Pretreatment of mice with geldanamycin (GA) 16 h before hemorrhage effectively inhibited the expression of the proteins KLF6 and iNOS, whereas caffeic acid phenethyl ester did not. GA pretreatment increased inducible heat shock protein (HSP) 70 but not HSP90 in both sham and hemorrhagic tissues. The overexpressed inducible HSP70 formed complexes with KLF6 and iNOS. These results suggest that GA may be therapeutically useful for reducing hemorrhage-induced injury when used as a presurgical treatment or when added to resuscitation fluids.
Kiang
Juliann G
JG
Department of Cellular Injury, Division of Military Casualty Research, Walter Reed Army Institute of Research, Silver Spring, MD 20910-7500, USA. Juliann.Kiang@na.amedd.army.mil
Bowman
Phillip D
PD
Wu
Brian W
BW
Hampton
Nyasa
N
Kiang
Andrew G
AG
Zhao
Baiteng
B
Juang
Yuang-Taung
YT
Atkins
James L
JL
Tsokos
George C
GC
D000818:Animals; D016227:Benzoquinones; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism*; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006470:Hemorrhage / Q000188:drug therapy* / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D000075723:Kruppel-Like Factor 6; D051741:Kruppel-Like Transcription Factors; D047029:Lactams, Macrocyclic; D008297:Male; D051379:Mice; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D011809:Quinones / Q000494:pharmacology*; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism
D016227:Benzoquinones; D004791:Enzyme Inhibitors; D018840:HSP70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C491358:Klf6 protein, mouse; D000075723:Kruppel-Like Factor 6; D051741:Kruppel-Like Transcription Factors; D047029:Lactams, Macrocyclic; D011518:Proto-Oncogene Proteins; D011809:Quinones; D015534:Trans-Activators; D014157:Transcription Factors; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D048031:JNK Mitogen-Activated Protein Kinases; C001277:geldanamycin