Short-term exercise training protects against doxorubicin-induced cardiac mitochondrial damage independent of HSP72

• Published in: American journal of physiology. Heart and circulatory physiology 2010-11, Vol.299 (5), p.H1515-H1524
• Main Authors: Kavazis, Andreas N, Smuder, Ashley J, Min, Kisuk, Tümer, Nihal, Powers, Scott K
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Apoptosis - drug effects; Calcium - metabolism; Cardiotoxins - adverse effects; Cardiotoxins - pharmacology; Cells; Doxorubicin - adverse effects; Doxorubicin - pharmacology; Enzymes; Exercise; Genotype & phenotype; Heart; HSP72 Heat-Shock Proteins - metabolism; Lipid Peroxides - metabolism; Male; Mitochondria, Heart - drug effects; Mitochondria, Heart - physiology; Mitochondrial Diseases - chemically induced; Mitochondrial Diseases - metabolism; Mitochondrial Diseases - prevention & control; Models, Animal; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - pathology; Oxidative Stress - drug effects; Physical Conditioning, Animal - physiology; Protein Isoforms - metabolism; Proteins; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species - metabolism; Toxicity; Tumors
• ISSN: 0363-6135; 1522-1539
• DOI: 10.1152/ajpheart.00585.2010

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.