| Short-term exercise training protects against doxorubicin-induced cardiac mitochondrial damage independent of HSP72. | |
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MedLine Citation:
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PMID: 20833957 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Doxorubicin (Dox) is an antitumor agent used in cancer treatment, but its clinical use is limited due to cardiotoxicity. Although exercise training can defend against Dox-mediated cardiac damage, the means for this cardioprotection remain unknown. To investigate the mechanism(s) responsible for exercise training-induced cardioprotection against Dox-mediated cardiotoxicity, we tested a two-pronged hypothesis: 1) exercise training protects against Dox-induced cardiotoxicity by preventing Dox-mediated mitochondrial damage/dysfunction and increased oxidative stress and 2) exercise training-induced cardiac expression of the inducible isoform of the 70-kDa heat shock protein 72 (HSP72) is essential to achieve exercise training-induced cardioprotection against Dox toxicity. Animals were randomly assigned to sedentary or exercise groups and paired with either placebo or Dox treatment (i.e., 20 mg/kg body wt ip Dox hydrochloride 24 h before euthanasia). Dox administration resulted in cardiac mitochondrial dysfunction, activation of proteases, and apoptosis. Exercise training increased cardiac antioxidant enzymes and HSP72 protein abundance and protected cardiac myocytes against Dox-induced mitochondrial damage, protease activation, and apoptosis. To determine whether exercise-induced expression of HSP72 in the heart is required for this cardioprotection, we utilized an innovative experimental strategy that successfully prevented exercise-induced increases in myocardial HSP72 levels. However, prevention of exercise-induced increases in myocardial HSP72 did not eliminate the exercise-induced cardioprotective phenotype that is resistant to Dox-mediated injury. Our results indicate that exercise training protects against the detrimental side effects of Dox in cardiac myocytes, in part, by protecting mitochondria against Dox-mediated damage. However, this exercise-induced cardioprotection is independent of myocardial HSP72 levels. Finally, our data are consistent with the concept that increases in cardiac mitochondrial antioxidant enzymes may contribute to exercise-induced cardioprotection. |
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Authors:
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Andreas N Kavazis; Ashley J Smuder; Kisuk Min; Nihal Tümer; Scott K Powers |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S. Date: 2010-09-10 |
Journal Detail:
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Title: American journal of physiology. Heart and circulatory physiology Volume: 299 ISSN: 1522-1539 ISO Abbreviation: Am. J. Physiol. Heart Circ. Physiol. Publication Date: 2010 Nov |
Date Detail:
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Created Date: 2010-11-01 Completed Date: 2010-11-29 Revised Date: 2011-11-01 |
Medline Journal Info:
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Nlm Unique ID: 100901228 Medline TA: Am J Physiol Heart Circ Physiol Country: United States |
Other Details:
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Languages: eng Pagination: H1515-24 Citation Subset: IM |
Affiliation:
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Applied Physiology and Kinesiology, University of Florida, USA. ak771@msstate.edu |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Apoptosis / drug effects Calcium / metabolism Cardiotoxins / adverse effects*, pharmacology Doxorubicin / adverse effects*, pharmacology HSP72 Heat-Shock Proteins / metabolism* Lipid Peroxides / metabolism Male Mitochondria, Heart / drug effects, physiology* Mitochondrial Diseases / chemically induced*, metabolism, prevention & control* Models, Animal Myocytes, Cardiac / drug effects, metabolism, pathology Oxidative Stress / drug effects Physical Conditioning, Animal / physiology* Protein Isoforms / metabolism Rats Rats, Sprague-Dawley Reactive Oxygen Species / metabolism |
| Grant Support | |
ID/Acronym/Agency:
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R01HL-067855/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Cardiotoxins; 0/HSP72 Heat-Shock Proteins; 0/Lipid Peroxides; 0/Protein Isoforms; 0/Reactive Oxygen Species; 23214-92-8/Doxorubicin; 7440-70-2/Calcium |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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