Accelerated onset of heart failure in mice during pressure overload with chronically decreased SERCA2 calcium pump activity.
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 approximately 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.
Schultz
Jo El J
Jel J
Dept. of Physiology and Cell Biology, The Ohio State Univ. College of Medicine, 304 Hamilton Hall, 1645 Neil Ave., Columbus, OH 43210, USA.
Glascock
Betty J
BJ
Witt
Sandra A
SA
Nieman
Michelle L
ML
Nattamai
Kalpana J
KJ
Liu
Lynne H
LH
Lorenz
John N
JN
Shull
Gary E
GE
Kimball
Thomas R
TR
Periasamy
Muthu
M
D000818:Animals; D002118:Calcium / Q000378:metabolism; D000252:Calcium-Transporting ATPases / Q000235:genetics* / Q000378:metabolism*; D006328:Cardiac Catheterization; D003971:Diastole; D004452:Echocardiography; D005260:Female; D006333:Heart Failure / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000503:physiopathology*; D017379:Hypertrophy, Left Ventricular / Q000000981:diagnostic imaging / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D013599:Systole
D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; C506946:ATP2A2 protein, human; C506947:Atp2a2 protein, mouse; D000252:Calcium-Transporting ATPases; D002118:Calcium