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1 Anesthesiology, University of Colorado Health Sciences Center, Denver, CO, USA
2 Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA
* To whom correspondence should be addressed. E-mail: Paul.Wischmeyer{at}UCHSC.edu.
Glutamine (GLN) has been shown to protect cells, tissues, and whole organisms from stress and injury. Enhanced expression of heat shock protein (HSP) has been hypothesized to be responsible for this protection. To date, no clear mechanistic data confirming this relationship exists. This study tested the hypothesis that GLN-mediated activation of the HSP pathway via heat shock factor-1 (HSF-1) is responsible for cellular protection. HSF-1 wild type and knock out mouse fibroblasts (HSF-1+/+ and HSF-1-/-) were used in all experiments. Cells were treated with GLN concentrations ranging from 0-16 mM and exposed to heat-stress injury in a concurrent treatment model. Cell viability assayed with MTS. HSP-70, HSP-25, and nuclear HSF-1 expression via Western Blotting. HSF-1/HSE binding via EMSA. GLN significantly attenuated heat-stress induced cell death in HSF-1+/+ cells in a dose dependent manner, however GLN's survival benefit was lost in HSF-1-/- cells. GLN led to a dose dependent increase in HSP-70 and HSP-25 expression following heat-stress. No inducible HSP expression was observed in HSF-1-/- cells. GLN increased unphosphorylated HSF-1 in the nucleus prior to heat-stress. This was accompanied by a GLN-mediated increase in HSF-1/HSE binding and nuclear content of phosphorylated HSF-1 following heat-stress. This is the first demonstration that GLN-mediated cellular protection following heat-stress injury is related to HSF-1 expression and cellular capacity to activate an HSP response. Further, the mechanism of GLN-mediated protection against injury appears to involve an increase in nuclear HSF-1 content prior to stress and increased HSF-1 promoter binding and phosphorylation.
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