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J. Biol. Chem., Vol. 275, Issue 26, 19521-19528, June 30, 2000
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From the Human beta cells exhibit increased resistance
against nitric oxide (NO) radicals as compared with rodent islet cells.
Here we tested whether endogenous heat shock protein 70 (hsp70)
accounts for the resistance of human cells. Stable transfection of the human beta cell line CM with an antisense hsp70 mRNA-expressing plasmid (ashsp70) caused selective suppression (>95%) of
spontaneously expressed hsp70 but not of hsc70 or GRP75 protein.
ashsp70 transfection abolished the resistance of CM cells to the NO
donors (Z)-1-
(2-(2-aminoethyl)-N-(2-ammonioethyl)amino)diazen-1-ium-1,2-diolate and
sodium nitroprusside and increased the proportions of necrotic cells
3-5-fold (p < 0.05) and of apoptotic cells about
2-fold (p < 0.01). Re-induction of hsp70 expression
by heat shock re-established resistance to NO toxicity. hsp70 did not
exert its protective effect at the level of membrane lipid integrity
because radical induced lipid peroxidation appeared independent of
hsp70 expression. However, after NO exposure only hsp70-deficient cells
showed significantly decreased mitochondrial activity, by 40-80%
(p < 0.01). These results suggest a key role of hsp70
in the natural resistance of human beta cells against NO induced
injury, by preserving mitochondrial function. These findings provide
important implications for the development of beta cell protective
strategies in type 1 diabetes and islet transplantation.
Natural Resistance of Human Beta Cells toward Nitric Oxide Is
Mediated by Heat Shock Protein 70*
§,§,,
,,, and§§
German Diabetes Research Institute at the
Heinrich-Heine-University Düsseldorf,
D-40225 Düsseldorf, Germany, ¶ Danish Cancer Society
Research Center, Division of Cancer Biology,
Copenhagen, DK-2100 Denmark, ** Department of Diabetes and
Metabolism, St. Bartholomew's Hospital Medical College,
EC1A 7BE London, United Kingdom, and the
Institute for Physiological Chemistry I,
Heinrich-Heine-University Düsseldorf,
D-40225 Düsseldorf, Germany
*
This work was supported by the Deutsche
Forschungsgemeinschaft, by the Bundesministerium für Gesundheit,
and by the Minister für Wissenschaft und Forschung des Landes
Nordrhein-Westfalen.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.
Supported by the Danish Cancer Society.
§§
To whom correspondence should be addressed: German Diabetes
Research Inst., Clinical Dept., Auf'm Hennekamp 65, D-40225
Düsseldorf, Germany. Tel.: 49-211-3382-643; Fax: 49-211-3382-606;
E-mail: kolb@dfi.uni-duesseldorf.de.
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