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Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/74476

Type: Journal article
Title: Chaperone heat shock protein 90 mobilization and hydralazine cytoprotection against acrolein-induced carbonyl stress
Author: Burcham, Philip Cyril
Raso, Albert
Kaminskas, Lisa Michelle
Citation: Molecular Pharmacology, 2012; 82(5):876-886
Publisher: American Society for Pharmacology and Experimental Therapeutics
Issue Date: 2012
ISSN: 0026-895X
School/Discipline: School of Medical Sciences : Pharmacology
Statement of
Responsibility: 
Philip C. Burcham, Albert Raso and Lisa M. Kaminskas
Abstract: Toxic carbonyls such as acrolein participate in many degenerative diseases. Although the nucleophilic vasodilatory drug hydralazine readily traps such species under “test-tube” conditions, whether these reactions adequately explain its efficacy in animal models of carbonyl-mediated disease is uncertain. We have previously shown that hydralazine attacks carbonyl-adducted proteins in an “adduct-trapping” reaction that appears to take precedence over direct “carbonyl-sequestering” reactions, but how this reaction conferred cytoprotection was unclear. This study explored the possibility that by increasing the bulkiness of acrolein-adducted proteins, adduct-trapping might alter the redistribution of chaperones to damaged cytoskeletal proteins that are known targets for acrolein. Using A549 lung adenocarcinoma cells, the levels of chaperones heat shock protein (Hsp) 40, Hsp70, Hsp90, and Hsp110 were measured in intermediate filament extracts prepared after a 3-h exposure to acrolein. Exposure to acrolein alone modestly increased the levels of all four chaperones. Coexposure to hydralazine (10–100 μM) strongly suppressed cell ATP loss while producing strong adduct-trapping in intermediate filaments. Most strikingly, hydralazine selectively boosted the levels of cytoskeletal-associated Hsp90, including a high-mass species that was sensitive to the Hsp90 inhibitor 17-N-allylamino-17-demethoxygeldanamycin. Biochemical fractionation of acrolein- and hydralazine-treated cells revealed that hydralazine likely promoted Hsp90 migration from cytosol into other subcellular compartments. A role for Hsp90 mobilization in cytoprotection was confirmed by the finding that brief heat shock treatment suppressed acute acrolein toxicity in A549 cells. Taken together, these findings suggest that by increasing the steric bulk of carbonyl-adducted proteins, adduct-trapping drugs trigger the intracellular mobilization of the key molecular chaperone Hsp90.
Rights: Copyright © 2012 The American Society for Pharmacology and Experimental Therapeutics
RMID: 0020122556
DOI: 10.1124/mol.112.078956
Appears in Collections:Pharmacology publications
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