Inhibition of Na(+)-H(+) exchange prevents hypertrophy, fibrosis,
and heart failure in beta(1)-adrenergic receptor transgenic mice
S. Engelhardt, L. Hein, U. Keller, K. Klambt, and M. Lohse. Circ Res, 90 (7):
814-9(April 2002)Engelhardt, Stefan Hein, Lutz Keller, Ursula Klambt, Kerstin Lohse,
Martin J Research Support, Non-U.S. Gov't United States Circulation
research Circ Res. 2002 Apr 19;90(7):814-9..
Abstract
Chronic stimulation of the beta(1)-adrenergic receptor leads to hypertrophy
and heart failure in beta(1)-adrenergic receptor transgenic mice
and contributes to disease progression in heart failure patients.
The cellular mechanisms underlying these detrimental effects are
largely unknown. In this study, we have identified the cardiac Na(+)-H(+)
exchanger (NHE1) as a novel mediator of adrenergically induced heart
failure. beta(1)-Adrenergic receptor transgenic mice showed upregulation
of both NHE1 mRNA (+140+/-6%) and protein (+42+/-19%). In order to
test whether increased NHE1 is causally related to beta(1)-adrenergic-induced
hypertrophy, fibrosis, and heart failure, beta(1)-adrenergic receptor
transgenic (TG) and wild-type (WT) littermates were treated with
a diet containing 6000 ppm of the NHE1 inhibitor cariporide or control
chow for 8 months. There was significant hypertrophy of cardiac myocytes
in beta(1)-adrenergic receptor transgenic mice (2.3-fold increase
in myocyte cross-sectional area), which was virtually absent in cariporide-fed
animals. Interstitial fibrosis was prominent throughout the left
ventricular wall in nontreated beta(1)-adrenergic receptor transgenic
mice (4.8-fold increase in collagen volume fraction); cariporide
treatment completely prevented this development of fibrosis. Left
ventricular catheterization showed that cariporide also prevented
the loss of contractile function in beta(1)-adrenergic receptor transgenic
mice: whereas untreated transgenic mice showed a significant decrease
in left ventricular contractility (5250+/-570 mm Hg/s TG versus 7360+/-540
mm Hg/s WT, dp/dt(max)), this decrease was completely prevented by
cariporide (8150+/-520 mm Hg/s TG cariporide). Inhibition of NHE1
prevented the development of heart failure in beta(1)-receptor transgenic
mice. We conclude that the cardiac Na(+)-H(+) exchanger 1 is essential
for the detrimental cardiac effects of chronic beta(1)-receptor stimulation
in the heart.
Engelhardt, Stefan Hein, Lutz Keller, Ursula Klambt, Kerstin Lohse,
Martin J Research Support, Non-U.S. Gov't United States Circulation
research Circ Res. 2002 Apr 19;90(7):814-9.
%0 Journal Article
%1 Engelhardt2002
%A Engelhardt, S.
%A Hein, L.
%A Keller, U.
%A Klambt, K.
%A Lohse, M. J.
%D 2002
%J Circ Res
%K & Administration Administration, Animal Animals Antiporter/*antagonists Blotting, Body Cardiomegaly/complications/physiopathology/*prevention Contraction/drug Disease Drug Dysfunction, Enzyme Expression Failure/complications/physiopathology/*prevention Fibrosis/complications/metabolism/*prevention Gene Guanidines/administration Heart Humans Inhibitors/administration Left/pathology/physiopathology/prevention Messenger/analysis/metabolism Mice Models, Myocardial Myocardium/metabolism/pathology Oral Organ RNA, Schedule Size/drug Sodium-Hydrogen Sulfones/administration Transgenic Ventricular Weight/drug Western beta-1/genetics/*metabolism control dosage effects effects/genetics inhibitors/genetics/metabolism Receptor Adrenergic
%N 7
%P 814-9
%T Inhibition of Na(+)-H(+) exchange prevents hypertrophy, fibrosis,
and heart failure in beta(1)-adrenergic receptor transgenic mice
%U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11964375
%V 90
%X Chronic stimulation of the beta(1)-adrenergic receptor leads to hypertrophy
and heart failure in beta(1)-adrenergic receptor transgenic mice
and contributes to disease progression in heart failure patients.
The cellular mechanisms underlying these detrimental effects are
largely unknown. In this study, we have identified the cardiac Na(+)-H(+)
exchanger (NHE1) as a novel mediator of adrenergically induced heart
failure. beta(1)-Adrenergic receptor transgenic mice showed upregulation
of both NHE1 mRNA (+140+/-6%) and protein (+42+/-19%). In order to
test whether increased NHE1 is causally related to beta(1)-adrenergic-induced
hypertrophy, fibrosis, and heart failure, beta(1)-adrenergic receptor
transgenic (TG) and wild-type (WT) littermates were treated with
a diet containing 6000 ppm of the NHE1 inhibitor cariporide or control
chow for 8 months. There was significant hypertrophy of cardiac myocytes
in beta(1)-adrenergic receptor transgenic mice (2.3-fold increase
in myocyte cross-sectional area), which was virtually absent in cariporide-fed
animals. Interstitial fibrosis was prominent throughout the left
ventricular wall in nontreated beta(1)-adrenergic receptor transgenic
mice (4.8-fold increase in collagen volume fraction); cariporide
treatment completely prevented this development of fibrosis. Left
ventricular catheterization showed that cariporide also prevented
the loss of contractile function in beta(1)-adrenergic receptor transgenic
mice: whereas untreated transgenic mice showed a significant decrease
in left ventricular contractility (5250+/-570 mm Hg/s TG versus 7360+/-540
mm Hg/s WT, dp/dt(max)), this decrease was completely prevented by
cariporide (8150+/-520 mm Hg/s TG cariporide). Inhibition of NHE1
prevented the development of heart failure in beta(1)-receptor transgenic
mice. We conclude that the cardiac Na(+)-H(+) exchanger 1 is essential
for the detrimental cardiac effects of chronic beta(1)-receptor stimulation
in the heart.
@article{Engelhardt2002,
abstract = {Chronic stimulation of the beta(1)-adrenergic receptor leads to hypertrophy
and heart failure in beta(1)-adrenergic receptor transgenic mice
and contributes to disease progression in heart failure patients.
The cellular mechanisms underlying these detrimental effects are
largely unknown. In this study, we have identified the cardiac Na(+)-H(+)
exchanger (NHE1) as a novel mediator of adrenergically induced heart
failure. beta(1)-Adrenergic receptor transgenic mice showed upregulation
of both NHE1 mRNA (+140+/-6%) and protein (+42+/-19%). In order to
test whether increased NHE1 is causally related to beta(1)-adrenergic-induced
hypertrophy, fibrosis, and heart failure, beta(1)-adrenergic receptor
transgenic (TG) and wild-type (WT) littermates were treated with
a diet containing 6000 ppm of the NHE1 inhibitor cariporide or control
chow for 8 months. There was significant hypertrophy of cardiac myocytes
in beta(1)-adrenergic receptor transgenic mice (2.3-fold increase
in myocyte cross-sectional area), which was virtually absent in cariporide-fed
animals. Interstitial fibrosis was prominent throughout the left
ventricular wall in nontreated beta(1)-adrenergic receptor transgenic
mice (4.8-fold increase in collagen volume fraction); cariporide
treatment completely prevented this development of fibrosis. Left
ventricular catheterization showed that cariporide also prevented
the loss of contractile function in beta(1)-adrenergic receptor transgenic
mice: whereas untreated transgenic mice showed a significant decrease
in left ventricular contractility (5250+/-570 mm Hg/s TG versus 7360+/-540
mm Hg/s WT, dp/dt(max)), this decrease was completely prevented by
cariporide (8150+/-520 mm Hg/s TG cariporide). Inhibition of NHE1
prevented the development of heart failure in beta(1)-receptor transgenic
mice. We conclude that the cardiac Na(+)-H(+) exchanger 1 is essential
for the detrimental cardiac effects of chronic beta(1)-receptor stimulation
in the heart.},
added-at = {2010-12-14T18:12:02.000+0100},
author = {Engelhardt, S. and Hein, L. and Keller, U. and Klambt, K. and Lohse, M. J.},
biburl = {https://www.bibsonomy.org/bibtex/2433ab839404e83e4937a1320b1ddafac/pharmawuerz},
endnotereftype = {Journal Article},
interhash = {f3ca17468460baa35384642e12ef7d49},
intrahash = {433ab839404e83e4937a1320b1ddafac},
issn = {1524-4571 (Electronic) 1524-4571 (Linking)},
journal = {Circ Res},
keywords = {& Administration Administration, Animal Animals Antiporter/*antagonists Blotting, Body Cardiomegaly/complications/physiopathology/*prevention Contraction/drug Disease Drug Dysfunction, Enzyme Expression Failure/complications/physiopathology/*prevention Fibrosis/complications/metabolism/*prevention Gene Guanidines/administration Heart Humans Inhibitors/administration Left/pathology/physiopathology/prevention Messenger/analysis/metabolism Mice Models, Myocardial Myocardium/metabolism/pathology Oral Organ RNA, Schedule Size/drug Sodium-Hydrogen Sulfones/administration Transgenic Ventricular Weight/drug Western beta-1/genetics/*metabolism control dosage effects effects/genetics inhibitors/genetics/metabolism Receptor Adrenergic},
month = {Apr 19},
note = {Engelhardt, Stefan Hein, Lutz Keller, Ursula Klambt, Kerstin Lohse,
Martin J Research Support, Non-U.S. Gov't United States Circulation
research Circ Res. 2002 Apr 19;90(7):814-9.},
number = 7,
pages = {814-9},
shorttitle = {Inhibition of Na(+)-H(+) exchange prevents hypertrophy, fibrosis,
and heart failure in beta(1)-adrenergic receptor transgenic mice},
timestamp = {2010-12-14T18:22:39.000+0100},
title = {Inhibition of Na(+)-H(+) exchange prevents hypertrophy, fibrosis,
and heart failure in beta(1)-adrenergic receptor transgenic mice},
url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11964375},
volume = 90,
year = 2002
}