Geldanamycin treatment inhibits hemorrhage-induced increases in KLF6 and iNOS expression in unresuscitated mouse organs: role of inducible HSP70

Abstract

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.

Hypoxia upregulates hypoxia inducible factor (HIF)-3α expression in lung epithelial cells: characterization and comparison with HIF-1α

“…Heidbreder et al [24] suggested that HIF-3α may contribute to protection during early periods of hypoxia and/or moderate hypoxia. In contrast, HIF-1α may confer protection against severe and/or prolonged hypoxia [3,24]. Our experiments did not find that Cell Research | www.cell-research.com…”

“…Low cellular oxygen tension is seen in pathological conditions including ischemia [1], inflammation [2], hemorrhage [3] and neoplasm [4]. A variety of systemic and cellular responses for homeostatic adaptations are provoked under these hypoxic conditions, including erythropoiesis, vasodilatation, angiogenesis and glycolysis.…”

Inducible heat shock protein 70 kD and inducible nitric oxide synthase in hemorrhage/resuscitation-induced injury

“…Sham-treated mouse organs displayed no changes in the basal levels of c-JUN, KLF6, and iNOS. In addition to changes in this series of stress-related proteins listed above, hemorrhage also increases cellular caspase-3 activity [14], reduces cellular ATP levels [14][15][16][17][18], and elevated mRNA of p38-MAPK, p53, and Bcl-2 [18]. Fig.…”

“…A full time-course study of the effect of hemorrhage on a series of stress-related proteins such as c-JUN, Kruppellike factor 6 (KLF6), iNOS, HSP-70i, and hypoxia inducible factor 1α (HIF-1α) has been reported in a hemorrhage mouse model [13]. Based on Western blot data obtained from mouse lung, jejunum, heart, kidney, liver, and brain, c-JUN, KLF6, iNOS, HSP-70i, and HIF-1α are up-regulated (Fig.…”

“…The albino mouse was subjected to a cardiac puncture and its 40% of total blood was removed. The mouse was then allowed for various periods of time to respond to the hemorrhage before a small portion of jejunum was dissected out for immunoblotting analysis [13]. The sham-operated mice were exposed to the same procedure except blood withdrawal.…”