Oxidant stress can cause tissue damage and is implicated in the pathogenesis of some myocardial injuries. Neutrophil activation during infection, drugs, and reperfusion all cause oxidant stress and all can be associated with myocardial injury. Defenses against oxidant stress such as Se (acting through glutathione peroxidase), vitamin E, glutathione, and taurine would be expected to protect the myocardium. Keshan disease is a cardiomyopathy which occurs in Se-deficient humans. In the first grant period we carried out detailed biochemical studies of the Chinese subjects at risk for this disease. We found that they have a Se deficiency which is less severe than previous studies, which used inappropriate controls, had suggested. These subjects were also mildly vitamin E deficient. We propose that Keshan disease results from mild combined Se-vitamin E deficiencies and oxidant stress--perhaps from infection. Minipigs were fed Se- and vitamin E-deficient diets which caused severe deficiencies. They developed cardiac necrosis and died acutely. None developed a dilated cardiomyopathy which is the most common form of Keshan disease. Rat hearts were perfused. Se-deficient hearts developed diastolic dysfunction at lower rates of H2O2 infusion than did control hearts. This demonstrates that Se protects heart function against oxidant stress. Also Se deficiency led to increased taurine excretion in the urine by rats. Because taurine is postulated to be an oxidant defense, its depletion could increase the susceptibility of the heart to oxidant injury. In the next grant period we propose to continue investigating the role of oxidant stress and oxidant defenses in cardiac injury. Systolic and diastolic function will be determined in the isolated perfused rat heart and in an in vivo model under control conditions and under stress by a number of oxidant substances. Control hearts and hearts depleted of Se, vitamin E, glutathione, and taurine will be studied. Studies in mice are proposed to develop a morphologic model of oxidant injury. The goal is to produce a dilated cardiomyopathy similar to Keshan disease. Dietary manipulations of oxidant defenses and of oxidants will be used in these experiments. The effect of Se deficiency on taurine metabolism will be studied in the rat and in man. Studies are proposed to examine tissue levels, renal transport, and distribution of radiolabeled taurine in rats. An experiment in Se-deficient Chinese is proposed to determine whether the Se deficiency present in them is associated with loss of taurine. If it is, that could contribute to the development of Keshan disease. These studies should indicate which nutrient-dependent oxidant defenses are most important in protecting the heart against several types of oxidant injury. This information will be useful in planning studies of oxidant stress-induced cardiac injury in patients.
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