Cardiac Phenotyping of Transgenic Mice Over-expressing Sarcoplasmic Reticulum Calcium ATPase Pump

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The Ohio State University

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Every year, approximately 40% of individuals in the United States die from heart failure. Pre-existing conditions such as diabetes and arrhythmia can lead to heart failure. Despite the number of individuals that develop heart failure, the underlying mechanisms are still not well understood. In order for cardiac contraction to occur, the myocardial cells uptake calcium from the cytosol into the sarcoplasmic reticulum (SR) via the sarcoplasmic reticulum ATPase pump (SERCA). With an increased SERCA pump, the cells can uptake and release more calcium, which may enhance cardiac fucntion. For this study, we hypothesized that (1) SERCA overexpression in the heart can be used to rescue the ventricular tachycardia caused by a depletion of calsquestrin, a buffer protein in the SR; (2) SERCA overexpression in the heart can be used to rescue cardiomyopathy that occurs during diabetes. Transgenic animal models were used for this study. In study 1, transgenic mice with SERCA overexpression were crossed with mice with calsquestrin depletion. In study 2, the SERCA overexpression mice along with their wild type littermates were made diabetic. Electrocardiographic recording was performed to detect arrhythmia in study 2. Cardiac function was measured by echocardiographic examination in both studies. Our data demonstrated that SERCA overexpression in the heart worsened ventricular arrhythmia and induced heart failure in mice with calsequestrin mutation. In addition, SERCA overexpression in the heart did not significantly improve cardiac function during diabetic cardiomyopathy. Overall this data suggests that SERCA overexpression in the heart does not rescue pre-existing conditions associated with arrhythmias and diabetic cardiomyopathy so individuals should be cautious when using SERCA gene therapy.



SERCA, CASQ2, calsequestrin, sarcoplasmic reticulum