1. LPS Increases Hepatic HIF-1α Protein and Expression of the HIF-1-Dependent Gene Aldolase A in Rats
- Author
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Scharte, Marion, Han, Xianonan, Uchiyama, Takashi, Tawadrous, Zakaria, Delude, Russell L., and Fink, Mitchell P.
- Subjects
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RATS , *CEREBRAL anoxia , *TRANSCRIPTION factors , *INFLAMMATORY mediators , *GROWTH factors - Abstract
Background: Cellular adaptation to hypoxia is mediated in part by the transcription factor hypoxia-inducible factor 1 (HIF-1). Accumulating data suggest that pro-inflammatory mediators can up-regulate HIF-1α protein expression and HIF-1 DNA-binding activity in the absence of hypoxia. Accordingly, we investigated HIF-1 mediated signaling in endotoxemic rats. Materials and methods: We studied three groups of male Sprague Dawley rats. Controls (N = 5) were injected i.p. with saline. Endotoxemic rats (N = 9) received a sublethal dose of lipopolysaccaride (Escherichia coli; 5 mg/kg, i.p.). A third group of rats (N = 5) received the HIF-1 stabilizing agent CoCl2 (14 mg/kg, i.p.) at T = 0 h and T = 16 h. At T = 18 h, liver microvascular perfusion was measured using laser Doppler flowmetry and hepatic tissue samples were obtained. RNA was isolated and mRNA levels of the HIF-1 dependent genes aldolase A and vascular endothelial growth factor (VEGF) were determined using quantitative real-time RT-PCR. HIF-1α content was estimated by immunoprecipitation followed by Western blotting. Results: HIF-1α increased in hepatic tissue after treatment with LPS or CoCl2. LPS markedly increased hepatic expression of aldolase A, but failed to alter expression of VEGF. CoCl2 increased aldolase A and VEGF mRNA expression. Although hepatic microvascular perfusion was comparable in saline- and LPS-treated rats, hepatic microvascular blood flow and aldolase A expression were significantly inversely correlated among endotoxemic rats (r = 0.773; P = 0.003). Conclusions: Increased expression of aldolase A in endotoxemic rats is mediated by both hypoxia-dependent and hypoxia-independent mechanisms. [Copyright &y& Elsevier]
- Published
- 2006
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