Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Haghighi, K; Schmidt, AG; Hoit, BD; Brittsan, AG; Yatani, A; Lester, JW; Zhai, J; Kimura, Y; Dorn, GW; MacLennan, DH; Kranias, EG.
Superinhibition of sarcoplasmic reticulum function by phospholamban induces cardiac contractile failure.
J Biol Chem. 2001; 276(26): 24145-24152.
Doi: 10.1074/jbc.M102403200
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- Co-Autor*innen der Med Uni Graz
- Schmidt Albrecht
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- Abstract:
- To determine whether selective impairment of cardiac sarcoplasmic reticulum (SR) Ca(2+) transport may drive the progressive functional deterioration leading to heart failure, transgenic mice, overexpressing a phospholamban Val(49) --> Gly mutant (2-fold), which is a superinhibitor of SR Ca(2+)-ATPase affinity for Ca(2+), were generated, and their cardiac phenotype was examined longitudinally. At 3 months of age, the increased EC(50) level of SR Ca(2+) uptake for Ca(2+) (0.67 +/- 0.09 microm) resulted in significantly higher depression of cardiomyocyte rates of shortening (57%), relengthening (31%), and prolongation of the Ca(2+) 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 beta-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 Ca(2+) cycling and cardiac remodeling leading to heart failure, with a gender-dependent influence on the time course of these alterations.
- Find related publications in this database (using NLM MeSH Indexing)
- Aging -
- Animals -
- Calcium - metabolism
- Calcium Channels, L-Type - physiology
- Calcium-Binding Proteins - genetics Calcium-Binding Proteins - physiology
- Calcium-Transporting ATPases - antagonists and 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 -