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Abstract The nitric oxide (NO) synthase inhibitor N ω -nitro- l -arginine ( l -NNA) inhibits heat stress (HS)-induced NO production and the inducible 70-kDa heat shock protein (HSP-70i) in many rodent organs. We used human intestinal epithelial T84 cells to characterize the inhibitory effect of l -NNA on HS-induced HSP-70i expression. Intracellular Ca 2+ concentration (Ca 2+ i ) was measured using fura-2, and protein kinase C (PKC), and PKA activities were determined. HS increased HSP-70i mRNA and protein in T84 cells exposed to 45°C for 10 min and allowed to recover for 6 h. l -NNA treatment for 1 h before HS inhibited the induction of HSP-70i mRNA and protein, with an IC 50 of 0.0471 ± 0.0007 μM. Because the HS-induced increase in HSP-70i mRNA and protein is Ca 2+ dependent, we measured Ca 2+ i after treating cells with l -NNA. l -NNA at 100 μM significantly decreased resting Ca 2+ i . Likewise, treatment with 1 μM GF-109203X or H-89 (inhibitors of PKC and PKA, respectively) for 30 min also significantly decreased Ca 2+ i and inhibited HS-induced increase in HSP-70i. GF-109203X- or H-89-treated cells failed to respond to l -NNA by further decreasing Ca 2+ i and HSP-70i. l -NNA effectively blocked heat shock factor-1 (HSF1) translocation from the cytosol to the nucleus, a process requiring PKC phosphorylation. These results suggest that l -NNA inhibits HSP-70i by reducing Ca 2+ i and decreasing PKC and PKA activity, thereby blocking HSF1 translocation from the cytosol to the nucleus. heat nitric oxide heat shock protein protein kinase C protein kinase A Footnotes This work was supported by Department of Defense Research Area Management II Science Technology Objective C and R. The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Department of the Army or Department of Defense. Address for reprint requests and other correspondence: J. G. Kiang, Dept. of Cellular Injury, Walter Reed Army Institute of Research, 503 Robert Glen Ave., Silver Spring, MD 20910-7500 (E-mail: Juliann.Kiang@na.amedd.army.mil ). The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “ advertisement ” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 10.1152/ajpgi.00138.2001 Copyright © 2002 the American Physiological Society
AJP - Gastrointestinal and Liver Physiology – The American Physiological Society
Published: Mar 1, 2002
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