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.

Endurance exercise provides cardioprotection against ischemia-reperfusion (I/R) injury. Exercise-induced cardioprotection is associated with increases in cytoprotective proteins, including heat shock protein 72 (HSP72) and increases in antioxidant enzyme activity. On the basis of the reported half-life of these putative cardioprotective proteins, we hypothesized that exercise-induced cardioprotection against I/R injury would be lost within days after cessation of exercise. To test this, male rats (4 mo) were randomly assigned to one of five experimental groups: 1). sedentary control, 2). exercise followed by 1 day of rest, 3). exercise followed by 3 days of rest, 4). exercise followed by 9 days of rest, and 5). exercise followed by 18 days of rest. Exercise-induced increases (P < 0.05) in left ventricular catalase activity and HSP72 were evident at 1 and 3 days postexercise. However, at 9 days postexercise, myocardial HSP72 and catalase levels declined to sedentary control values. To evaluate cardioprotection during recovery from I/R, hearts were isolated, placed in working heart mode, and subjected to 20.5 min of global ischemia followed by 30 min of reperfusion. Compared with sedentary controls, exercised animals sustained less I/R injury as evidenced by maintenance of a higher (P < 0.05) percentage of preischemia cardiac work during reperfusion at 1, 3, and 9 days postexercise. The exercise-induced cardioprotection vanished by 18 days after exercise cessation. On the basis of the time course of the loss of cardioprotection and the return of HSP72 and catalase to preexercise levels, we conclude that HSP72 and catalase are not essential for exercise-induced protection during myocardial stunning. Therefore, other cytoprotective molecules are responsible for providing protection during I/R.

Abstract-Extracellular superoxide dismutase (SOD) contributes only a small fraction to total SOD activity in the normal heart but is strategically located to scavenge free radicals in the extracellular compartment. To examine the physiological significance of extracellular SOD in the response of the heart to hemodynamic stress, we studied the effect of extracellular SOD deficiency on transverse aortic constriction (TAC)-induced left ventricular remodeling. Under unstressed conditions extracellular SOD deficiency had no effect on myocardial total SOD activity, the ratio of glutathione:glutathione disulfide, nitrotyrosine content, or superoxide anion production but resulted in small but significant increases in myocardial fibrosis and ventricular mass. In response to TAC for 6 weeks, extracellular SOD-deficient mice developed more severe left ventricular hypertrophy (heart weight increased 2.56-fold in extracellular SOD-deficient mice as compared with 1.99-fold in wild-type mice) and pulmonary congestion (lung weight increased 2.92-fold in extracellular SOD-deficient mice as compared with 1.84-fold in wild-type mice). Extracellular SOD-deficient mice also had more ventricular fibrosis, dilation, and a greater reduction of left ventricular fractional shortening and rate of pressure development after TAC. TAC resulted in greater increases of ventricular collagen I, collagen III, matrix metalloproteinase-2, matrix metalloproteinase-9, nitrotyrosine, and superoxide anion production. TAC also resulted in a greater decrease of the ratio of glutathione:glutathione disulfide in extracellular SOD-deficient mice. The finding that extracellular SOD deficiency had minimal impact on myocardial overall SOD activity but exacerbated TAC induced myocardial oxidative stress, hypertrophy, fibrosis, and dysfunction indicates that the distribution of extracellular SOD in the extracellular space is critically important in protecting the heart against pressure overload. Key Words: extracellular SOD Ⅲ hypertrophy Ⅲ congestive heart failure Ⅲ oxidative stress Ⅲ ventricular fibrosis Ⅲ MMP C ongestive heart failure (CHF) because of a variety of conditions is associated with depressed antioxidant reserves and increased products of oxygen free radical reactions, suggesting that oxidative stress might contribute to contractile dysfunction in the failing heart. 1 Superoxide dismutase (SOD) is the first line of defense against free radical attack. Three SOD isozymes have been identified, including a copper/zinc-containing SOD (SOD1), which is primarily cytosolic in location, a mitochondrial manganese SOD (SOD2), and an extracellular SOD (SOD3). SOD3 is a glycoprotein secreted into the extracellular fluid by fibroblasts that bind to sulfated polysaccharides, such as heparin and heparan sulfate, 2,3 as well as to other matrix components. 4,5 As a result, SOD3 binds to the surface of endothelial cells and the extracellular matrix, which has a high abundance of heparan sulfate. 6 Several recent studies have demonstrated that SOD3 expression is decre...