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Superinhibition of Sarcoplasmic Reticulum Function by Phospholamban Induces Cardiac Contractile Failure

To determine whether selective impairment of cardiac sarcoplasmic reticulum (SR) Ca2+ transport may drive the progressive functional deterioration leading to heart failure, transgenic mice, overexpressing a phospholamban Val49 → Gly mutant (2-fold), which is a superinhibitor of SR Ca2+-ATPase affini...

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Published in:The Journal of biological chemistry 2001-06, Vol.276 (26), p.24145-24152
Main Authors: Haghighi, Kobra, Schmidt, Albrecht G., Hoit, Brian D., Brittsan, Angela G., Yatani, Atsuko, Lester, James W., Zhai, Jing, Kimura, Yoshihiro, Dorn, Gerald W., MacLennan, David H., Kranias, Evangelia G.
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container_issue 26
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container_title The Journal of biological chemistry
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creator Haghighi, Kobra
Schmidt, Albrecht G.
Hoit, Brian D.
Brittsan, Angela G.
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Kimura, Yoshihiro
Dorn, Gerald W.
MacLennan, David H.
Kranias, Evangelia G.
description To determine whether selective impairment of cardiac sarcoplasmic reticulum (SR) Ca2+ transport may drive the progressive functional deterioration leading to heart failure, transgenic mice, overexpressing a phospholamban Val49 → Gly mutant (2-fold), which is a superinhibitor of SR Ca2+-ATPase affinity for Ca2+, were generated, and their cardiac phenotype was examined longitudinally. At 3 months of age, the increased EC50 level of SR Ca2+ uptake for Ca2+ (0.67 ± 0.09 μm) resulted in significantly higher depression of cardiomyocyte rates of shortening (57%), relengthening (31%), and prolongation of the Ca2+ signal decay time (165%) than overexpression (2-fold) of wild type phospholamban (68%, 64%, and 125%, respectively), compared with controls (100%). Echocardiography also revealed significantly depressed function and impaired β-adrenergic responses in mutant hearts. The depressed contractile parameters were associated with left ventricular remodeling, recapitulation of fetal gene expression, and hypertrophy, which progressed to dilated cardiomyopathy with interstitial tissue fibrosis and death by 6 months in males. Females also had ventricular hypertrophy at 3 months but exhibited normal systolic function up to 12 months of age. These results suggest a causal relationship between defective SR Ca2+ cycling and cardiac remodeling leading to heart failure, with a gender-dependent influence on the time course of these alterations.
doi_str_mv 10.1074/jbc.M102403200
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identifier ISSN: 0021-9258
ispartof The Journal of biological chemistry, 2001-06, Vol.276 (26), p.24145-24152
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source ScienceDirect Journals
subjects Aging
Animals
Calcium - metabolism
Calcium Channels, L-Type - physiology
Calcium-Binding Proteins - genetics
Calcium-Binding Proteins - physiology
Calcium-Transporting ATPases - antagonists & inhibitors
Cardiomegaly - etiology
Cardiomegaly - metabolism
Cardiomegaly - physiopathology
Cells, Cultured
Echocardiography
Female
Heart Failure - etiology
Heart Failure - metabolism
Heart Failure - physiopathology
Male
Mice
Mice, Transgenic
Myocardial Contraction
Myocardium - metabolism
Myocardium - pathology
Point Mutation
Sarcoplasmic Reticulum - physiology
Sarcoplasmic Reticulum Calcium-Transporting ATPases
Sex Factors
Survival Rate
title Superinhibition of Sarcoplasmic Reticulum Function by Phospholamban Induces Cardiac Contractile Failure
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