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Am J Physiol Heart Circ Physiol 286: H1146-H1153, 2004. First published November 20, 2003; doi:10.1152/ajpheart.00720.2003
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Accelerated onset of heart failure in mice during pressure overload with chronically decreased SERCA2 calcium pump activity

Jo El J. Schultz,1,2 Betty J. Glascock,3 Sandra A. Witt,3 Michelle L. Nieman,4,5 Kalpana J. Nattamai,6 Lynne H. Liu,6 John N. Lorenz,4,5 Gary E. Shull,1 Thomas R. Kimball,3 and Muthu Periasamy6

1Department of Molecular Genetics, Biochemistry, and Microbiology, 2Department of Pharmacology and Cell Biophysics, 4Department of Molecular and Cellular Physiology; 5Noninvasive Cardiac Imaging and Hemodynamic Research Laboratory, Division of Cardiology, and 3Department of Pediatrics, Children's Hospital Medical Center, Cincinnati 45229; and 6Department of Physiology and Cell Biology, The Ohio State University, Columbus, Ohio 43210

Submitted 28 July 2003 ; accepted in final form 10 November 2003

We recently developed a mouse model with a single functional allele of Serca2 (Serca2+/–) that shows impaired cardiac contractility and relaxation without overt heart disease. The goal of this study was to test the hypothesis that chronic reduction in sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA)2 levels in combination with an increased hemodynamic load will result in an accelerated pathway to heart failure. Age-matched wild-type and Serca2+/– mice were subjected to 10 wk of pressure overload via transverse aortic coarctation surgery. Cardiac hypertrophy and heart failure were assessed by echocardiography, gravimetry/histology, hemodynamics, and Western blotting analyses. Our results showed that ~64% of coarcted Serca2+/– mice were in heart failure compared with 0% of coarcted wild-type mice (P < 0.05). Overall, morbidity and mortality were greatly increased in Serca2+/– mice under pressure overload. Echocardiography assessment revealed a significant increase in left ventricular (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 and/or function compared with coarcted wild-type 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 with noncoarcted and coarcted wild-type mice. Our findings suggest that reduction in SERCA2 levels in combination with an increased hemodynamic load results in an accelerated pathway to heart failure.

sarco(endo)plasmic reticulum calcium-adenosine 5'-triphosphatase pump; knockout mice; echocardiography; cardiac dysfunction


Address for reprint requests and other correspondence: M. Periasamy, Dept. of Physiology and Cell Biology, The Ohio State Univ. College of Medicine, 304 Hamilton Hall, 1645 Neil Ave., Columbus, OH 43210 (E-mail: periasamy.1{at}osu.edu).




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