Accelerated onset of heart failure in mice during pressure overload with chronically decreased SERCA2 calcium pump activity

• Published in: American journal of physiology. Heart and circulatory physiology 2004-03, Vol.286 (3), p.H1146-H1153
• Main Authors: Schultz, Jo El J, Glascock, Betty J, Witt, Sandra A, Nieman, Michelle L, Nattamai, Kalpana J, Liu, Lynne H, Lorenz, John N, Shull, Gary E, Kimball, Thomas R, Periasamy, Muthu
• Format: Article
• Language: English
• Subjects: Animals; Calcium - metabolism; Calcium-Transporting ATPases - genetics; Calcium-Transporting ATPases - metabolism; Cardiac Catheterization; Diastole; Echocardiography; Female; Heart Failure - diagnostic imaging; Heart Failure - metabolism; Heart Failure - physiopathology; Hypertrophy, Left Ventricular - diagnostic imaging; Hypertrophy, Left Ventricular - metabolism; Hypertrophy, Left Ventricular - physiopathology; Male; Mice; Mice, Knockout; Phenotype; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Systole
• ISSN: 0363-6135; 1522-1539
• DOI: 10.1152/ajpheart.00720.2003

1 Department of Molecular Genetics, Biochemistry, and Microbiology, 2 Department of Pharmacology and Cell Biophysics, 4 Department of Molecular and Cellular Physiology; 5 Noninvasive Cardiac Imaging and Hemodynamic Research Laboratory, Division of Cardiology, and 3 Department of Pediatrics, Children's Hospital Medical Center, Cincinnati 45229; and 6 Department 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 Ca 2+ -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., Colum