Exercise-induced protection against myocardial apoptosis and necrosis: MnSOD, calcium-handling proteins, and calpain.
Exercise provides protection against myocardial ischemia-reperfusion (IR) injury. Understanding the mechanisms of this protection may lead to new interventions for the prevention and/or treatment of heart disease. Although presently these mechanisms are not well understood, reports suggest that manganese superoxide dismutase (MnSOD) and calpain may be critical mediators of this protection. We hypothesized that an exercise-induced increase in MnSOD would provide cardioprotection by attenuating IR-induced oxidative modification to critical Ca(2+)-handling proteins, thereby decreasing calpain-mediated cleavage of these and other proteins attenuating cardiomyocyte death. After IR, myocardial apoptosis and infarct size were significantly reduced in hearts of exercised animals compared with sedentary controls. In addition, exercise prevented IR-induced calpain activation as well as the oxidative modification and calpain-mediated degradation of myocardial Ca(2+)-handling proteins (L-type Ca(2+) channels, phospholamban, and sarcoplasmic/endoplasmic reticulum calcium ATPase). Further, IR-induced activation of proapoptotic proteins was attenuated in exercised animals. Importantly, prevention of the exercise-induced increase in MnSOD activity via antisense oligonucleotides greatly attenuated the cardioprotection conferred by exercise. These results suggest that MnSOD provides cardioprotection by attenuating IR-induced oxidation and calpain-mediated degradation of myocardial Ca(2+)-handling proteins, thereby preventing myocardial apoptosis and necrosis.
French
Joel P
JP
Department of Applied Physiology and Kinesiology, Center for Exercise Science, University of Florida, Gainesville, Florida, USA. frenc147@umn.edu
Hamilton
Karyn L
KL
Quindry
John C
JC
Lee
Youngil
Y
Upchurch
Patrick A
PA
Powers
Scott K
SK
D000818:Animals; D017209:Apoptosis; D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism*; D002154:Calpain / Q000378:metabolism*; D053454:Caspase 12 / Q000378:metabolism; D008297:Male; D008955:Models, Cardiovascular; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D009336:Necrosis; D016376:Oligonucleotides, Antisense / Q000235:genetics / Q000494:pharmacology; D005082:Physical Exertion / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013482:Superoxide Dismutase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
D051023:BH3 Interacting Domain Death Agonist Protein; C494816:Bid protein, rat; D002135:Calcium-Binding Proteins; D016376:Oligonucleotides, Antisense; D013482:Superoxide Dismutase; D002154:Calpain; C506443:Casp12 protein, rat; D053454:Caspase 12