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1 Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA; Department of Pharmacology and Cell Biophysics, University of Cincinnati, Cincinnati, Ohio, USA
2 Department of Pediatrics, Children's Hospital Medical Center, Cincinnati, Ohio, USA
3 Department of Molecular and Cellular Physiology, and Division of Cardiology, University of Cincinnati College of Medicine and Noninvasive Cardiac Imaging and Hemodynamic Research Laboratory, Cincinnati, Ohio, USA
4 Department of Physiology and Cell Biology, The Ohio State University, Columbus, Ohio, USA
5 Department of Internal Medicine Division of Cardiology, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
6 Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
7 Department of Internal Medicine Division of Cardiology, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA; Department of Physiology and Cell Biology, The Ohio State University, Columbus, Ohio, USA
* To whom correspondence should be addressed. E-mail: periasamy.1{at}osu.edu.
We recently developed a mouse model with a single functional allele of Serca2 (+/-) which show impaired cardiac contractility and relaxation without overt heart disease. The goal of this study was to test the hypothesis that chronic reduction in SERCA2 levels in combination with an increased hemodynamic load will result in an accelerated pathway to heart failure. Age matched Wildtype and Serca2+/- mice were subjected to 10 weeks of pressure overload via transverse aortic coarctation surgery. Cardiac hypertrophy and heart failure were assessed using Echocardiography, gravimetry/histology, hemodynamic, and western blotting analyses. Our results showed that ~64% of coarcted Serca2+/- mice were in heart failure compared to 0% of coarcted wildtype mice (p<0.05). Overall, morbidity and mortality were greatly increased in Serca2+/- mice under pressure overload. Echocardiography assessment revealed a significant increase in LV mass, and LV hypertrophy in coarcted Serca2+/- mice converted from a concentric to an eccentric pattern, similar to that seen in human heart failure. Coarcted Serca2+/- mice had decreased contractile/systolic and relaxation/diastolic performance/function compared to coarcted wildtype mice (p<0.05), despite a similar duration and degree of pressure overload. SERCA2a protein levels were significantly reduced (>50%) in coarcted Serca2+/- mice compared to noncoarcted and coarcted wildtype mice. Our findings suggest that reduction in SERCA2 levels in combination with an increased hemodynamic load result in an accelerated pathway to heart failure.
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