Document Detail

Short-term exercise training protects against doxorubicin-induced cardiac mitochondrial damage independent of HSP72.
MedLine Citation:
PMID:  20833957     Owner:  NLM     Status:  MEDLINE    
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.
Andreas N Kavazis; Ashley J Smuder; Kisuk Min; Nihal Tümer; Scott K Powers
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Publication Detail:
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:
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:
Created Date:  2010-11-01     Completed Date:  2010-11-29     Revised Date:  2013-05-28    
Medline Journal Info:
Nlm Unique ID:  100901228     Medline TA:  Am J Physiol Heart Circ Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  H1515-24     Citation Subset:  IM    
Applied Physiology and Kinesiology, University of Florida, USA.
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MeSH Terms
Apoptosis / drug effects
Calcium / metabolism
Cardiotoxins / adverse effects*,  pharmacology
Doxorubicin / adverse effects*,  pharmacology
HSP72 Heat-Shock Proteins / metabolism*
Lipid Peroxides / metabolism
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, Sprague-Dawley
Reactive Oxygen Species / metabolism
Grant Support
Reg. No./Substance:
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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