Altered calcium handling is critically involved in the cardiotoxic
effects of chronic beta-adrenergic stimulation
S. Engelhardt, L. Hein, V. Dyachenkow, E. Kranias, G. Isenberg, и M. Lohse. Circulation, 109 (9):
1154-60(марта 2004)Engelhardt, Stefan Hein, Lutz Dyachenkow, Vitaly Kranias, Evangelia
G Isenberg, Gerrit Lohse, Martin J HL26057/HL/NHLBI NIH HHS/United
States HL52318/HL/NHLBI NIH HHS/United States HL64018/HL/NHLBI NIH
HHS/United States Research Support, Non-U.S. Gov't Research Support,
U.S. Gov't, P.H.S. United States Circulation Circulation. 2004 Mar
9;109(9):1154-60. Epub 2004 Feb 16..
Аннотация
BACKGROUND: Chronic adrenergic stimulation leads to cardiac hypertrophy
and heart failure in experimental models and contributes to the progression
of heart failure in humans. The pathways mediating the detrimental
effects of chronic beta-adrenergic stimulation are only partly understood.
We investigated whether genetic modification of calcium handling
through deletion of phospholamban in mice would affect the development
of heart failure in mice with transgenic overexpression of the beta1-adrenergic
receptor. METHODS AND RESULTS: We crossed beta1-adrenergic receptor
transgenic (beta1TG) mice with mice homozygous for a targeted deletion
of the phospholamban gene (PLB-/-). Phospholamban ablation dramatically
enhanced survival of beta1TG mice. The decrease of left ventricular
contractility typically observed in beta1TG mice was reverted back
to normal by phospholamban ablation. Cardiac hypertrophy and fibrosis
were significantly inhibited in beta1TG/PLB-/- mice compared with
beta1TG mice, and the heart failure-specific gene expression pattern
was normalized. Analysis of intracellular calcium transients revealed
increased diastolic calcium levels and decreased rate constants of
diastolic calcium decline in beta1TG mice. In beta1TG/PLB-/- mice,
diastolic calcium concentration was normal and rate constants of
diastolic calcium decline were greater than in wild-type mice. CONCLUSIONS:
We conclude that modification of abnormal calcium handling in beta1TG
mice through ablation of phospholamban resulted in a rescue of functional,
morphological, and molecular characteristics of heart failure in
beta1-adrenergic receptor-transgenic mice. These results imply altered
calcium handling as critical for the detrimental effects of beta1-adrenergic
signaling.
Engelhardt, Stefan Hein, Lutz Dyachenkow, Vitaly Kranias, Evangelia
G Isenberg, Gerrit Lohse, Martin J HL26057/HL/NHLBI NIH HHS/United
States HL52318/HL/NHLBI NIH HHS/United States HL64018/HL/NHLBI NIH
HHS/United States Research Support, Non-U.S. Gov't Research Support,
U.S. Gov't, P.H.S. United States Circulation Circulation. 2004 Mar
9;109(9):1154-60. Epub 2004 Feb 16.
%0 Journal Article
%1 Engelhardt2004
%A Engelhardt, S.
%A Hein, L.
%A Dyachenkow, V.
%A Kranias, E. G.
%A Isenberg, G.
%A Lohse, M. J.
%D 2004
%J Circulation
%K *Calcium Analysis Animals Calcium-Binding Calcium/metabolism/physiology Cardiomegaly/pathology Cardiomyopathy, Contraction Dilated/*etiology/metabolism/pathology Edema/pathology Fibrosis Function, Humans Knockout Left Messenger/metabolism Mice Myocardial Myocardium/metabolism/pathology Proteins/genetics Pulmonary RNA, Signaling Survival Transgenic Ventricular beta-1/genetics/*metabolism Receptor Adrenergic
%N 9
%P 1154-60
%T Altered calcium handling is critically involved in the cardiotoxic
effects of chronic beta-adrenergic stimulation
%U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=14967726
%V 109
%X BACKGROUND: Chronic adrenergic stimulation leads to cardiac hypertrophy
and heart failure in experimental models and contributes to the progression
of heart failure in humans. The pathways mediating the detrimental
effects of chronic beta-adrenergic stimulation are only partly understood.
We investigated whether genetic modification of calcium handling
through deletion of phospholamban in mice would affect the development
of heart failure in mice with transgenic overexpression of the beta1-adrenergic
receptor. METHODS AND RESULTS: We crossed beta1-adrenergic receptor
transgenic (beta1TG) mice with mice homozygous for a targeted deletion
of the phospholamban gene (PLB-/-). Phospholamban ablation dramatically
enhanced survival of beta1TG mice. The decrease of left ventricular
contractility typically observed in beta1TG mice was reverted back
to normal by phospholamban ablation. Cardiac hypertrophy and fibrosis
were significantly inhibited in beta1TG/PLB-/- mice compared with
beta1TG mice, and the heart failure-specific gene expression pattern
was normalized. Analysis of intracellular calcium transients revealed
increased diastolic calcium levels and decreased rate constants of
diastolic calcium decline in beta1TG mice. In beta1TG/PLB-/- mice,
diastolic calcium concentration was normal and rate constants of
diastolic calcium decline were greater than in wild-type mice. CONCLUSIONS:
We conclude that modification of abnormal calcium handling in beta1TG
mice through ablation of phospholamban resulted in a rescue of functional,
morphological, and molecular characteristics of heart failure in
beta1-adrenergic receptor-transgenic mice. These results imply altered
calcium handling as critical for the detrimental effects of beta1-adrenergic
signaling.
@article{Engelhardt2004,
abstract = {BACKGROUND: Chronic adrenergic stimulation leads to cardiac hypertrophy
and heart failure in experimental models and contributes to the progression
of heart failure in humans. The pathways mediating the detrimental
effects of chronic beta-adrenergic stimulation are only partly understood.
We investigated whether genetic modification of calcium handling
through deletion of phospholamban in mice would affect the development
of heart failure in mice with transgenic overexpression of the beta1-adrenergic
receptor. METHODS AND RESULTS: We crossed beta1-adrenergic receptor
transgenic (beta1TG) mice with mice homozygous for a targeted deletion
of the phospholamban gene (PLB-/-). Phospholamban ablation dramatically
enhanced survival of beta1TG mice. The decrease of left ventricular
contractility typically observed in beta1TG mice was reverted back
to normal by phospholamban ablation. Cardiac hypertrophy and fibrosis
were significantly inhibited in beta1TG/PLB-/- mice compared with
beta1TG mice, and the heart failure-specific gene expression pattern
was normalized. Analysis of intracellular calcium transients revealed
increased diastolic calcium levels and decreased rate constants of
diastolic calcium decline in beta1TG mice. In beta1TG/PLB-/- mice,
diastolic calcium concentration was normal and rate constants of
diastolic calcium decline were greater than in wild-type mice. CONCLUSIONS:
We conclude that modification of abnormal calcium handling in beta1TG
mice through ablation of phospholamban resulted in a rescue of functional,
morphological, and molecular characteristics of heart failure in
beta1-adrenergic receptor-transgenic mice. These results imply altered
calcium handling as critical for the detrimental effects of beta1-adrenergic
signaling.},
added-at = {2010-12-14T18:12:02.000+0100},
author = {Engelhardt, S. and Hein, L. and Dyachenkow, V. and Kranias, E. G. and Isenberg, G. and Lohse, M. J.},
biburl = {https://www.bibsonomy.org/bibtex/2658fc473a9125d652522d0ab1f9027b5/pharmawuerz},
endnotereftype = {Journal Article},
interhash = {3e6ce109b75c5c2481758809499928de},
intrahash = {658fc473a9125d652522d0ab1f9027b5},
issn = {1524-4539 (Electronic) 1524-4539 (Linking)},
journal = {Circulation},
keywords = {*Calcium Analysis Animals Calcium-Binding Calcium/metabolism/physiology Cardiomegaly/pathology Cardiomyopathy, Contraction Dilated/*etiology/metabolism/pathology Edema/pathology Fibrosis Function, Humans Knockout Left Messenger/metabolism Mice Myocardial Myocardium/metabolism/pathology Proteins/genetics Pulmonary RNA, Signaling Survival Transgenic Ventricular beta-1/genetics/*metabolism Receptor Adrenergic},
month = {Mar 9},
note = {Engelhardt, Stefan Hein, Lutz Dyachenkow, Vitaly Kranias, Evangelia
G Isenberg, Gerrit Lohse, Martin J HL26057/HL/NHLBI NIH HHS/United
States HL52318/HL/NHLBI NIH HHS/United States HL64018/HL/NHLBI NIH
HHS/United States Research Support, Non-U.S. Gov't Research Support,
U.S. Gov't, P.H.S. United States Circulation Circulation. 2004 Mar
9;109(9):1154-60. Epub 2004 Feb 16.},
number = 9,
pages = {1154-60},
shorttitle = {Altered calcium handling is critically involved in the cardiotoxic
effects of chronic beta-adrenergic stimulation},
timestamp = {2010-12-14T18:22:39.000+0100},
title = {Altered calcium handling is critically involved in the cardiotoxic
effects of chronic beta-adrenergic stimulation},
url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=14967726},
volume = 109,
year = 2004
}