HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 293/5/H3111    most recent 00328.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (8) Citing Articles via Google Scholar Google Scholar Articles by Turakhia, S. Articles by Ilangovan, G. Search for Related Content PubMed PubMed Citation Articles by Turakhia, S. Articles by Ilangovan, G.

Doxorubicin-induced cardiotoxicity: direct correlation of cardiac fibroblast and H9c2 cell survival and aconitase activity with heat shock protein 27

¹Division of Cardiovascular Medicine, Department of Internal Medicine, Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio; ²Division of Critical Care Medicine, Cincinnati Children's Hospital and the Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio

Submitted 15 March 2007 ; accepted in final form 14 September 2007

The use of doxorubicin (Dox) and its derivatives as chemotherapeutic drugs to treat patients with cancer causes dilated cardiomyopathy and congestive heart failure due to Dox-induced cardiotoxicity. In this work, using heat shock factor-1 wild-type (HSF-1^+/+) and HSF-1 knockout (HSF-1^–/–) mouse fibroblasts and embryonic rat heart-derived cardiac H9c2 cells, we show that the magnitude of protection from Dox-induced toxicity directly correlates with the level of the heat shock protein 27 (HSP27). Western blot analysis of normal and heat-shocked cells showed the maximum expression of HSP27 in heat-shocked cardiac H9c2 cells and no HSP27 in HSF-1^–/– cells (normal or heat-shocked). Correspondingly, the cell viability, measured [with (3,4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay] after treatment with various concentrations of Dox, was the highest in heat-shocked H9c2 cells and the lowest in HSF-1^–/– cells. Depleting HSP27 in cardiac H9c2 cells by small interfering (si)RNA also reduced the viability against Dox, confirming that HSP27 does protect cardiac cells against the Dox-induced toxicity. The cells that have lower HSP27 levels such as HSF-1^–/–, were found to be more susceptible for aconitase inactivation. Based on these results we propose a novel mechanism that HSP27 plays an important role in protecting aconitase from Dox-generated O₂^–, by increasing SOD activity. Such a protection of aconitase by HSP27 eliminates the catalytic recycling of aconitase released Fe(II) and its deleterious effects in cardiac cells.

superoxide dismutase

This article has been cited by other articles:

				M. C. Jaramillo, J. B. Frye, J. D. Crapo, M. M. Briehl, and M. E. Tome Increased Manganese Superoxide Dismutase Expression or Treatment with Manganese Porphyrin Potentiates Dexamethasone-Induced Apoptosis in Lymphoma Cells Cancer Res., July 1, 2009; 69(13): 5450 - 5457. [Abstract] [Full Text] [PDF]

				C. D. Venkatakrishnan, K. Dunsmore, H. Wong, S. Roy, C. K. Sen, A. Wani, J. L. Zweier, and G. Ilangovan HSP27 regulates p53 transcriptional activity in doxorubicin-treated fibroblasts and cardiac H9c2 cells: p21 upregulation and G2/M phase cell cycle arrest Am J Physiol Heart Circ Physiol, April 1, 2008; 294(4): H1736 - H1744. [Abstract] [Full Text] [PDF]