Abnormal cardiac ryanodine receptor (RyR2) function is recognized
as an important factor in the pathogenesis of heart failure (HF).
However, the specific molecular causes underlying RyR2 defects in
HF remain poorly understood. In the present study, we used a canine
model of chronic HF to test the hypothesis that the HF-related alterations
in RyR2 function are caused by posttranslational modification by
reactive oxygen species generated in the failing heart. Experimental
approaches included imaging of cytosolic (Ca(2+)(c)) and sarcoplasmic
reticulum (SR) luminal Ca(2+) (Ca(2+)SR) in isolated intact and
permeabilized ventricular myocytes and single RyR2 channel recording
using the planar lipid bilayer technique. The ratio of reduced to
oxidized glutathione, as well as the level of free thiols on RyR2
decreased markedly in failing versus control hearts consistent with
increased oxidative stress in HF. RyR2-mediated SR Ca(2+) leak was
significantly enhanced in permeabilized myocytes, resulting in reduced
Ca(2+)(SR) in HF compared to control cells. Both SR Ca(2+) leak
and Ca(2+)(SR) were partially normalized by treating HF myocytes
with reducing agents. Conversely, oxidizing agents accelerated SR
Ca(2+) leak and decreased Ca(2+)(SR) in cells from normal hearts.
Moreover, exposure to antioxidants significantly improved intracellular
Ca(2+)-handling parameters in intact HF myocytes. Single RyR2 channel
activity was significantly higher in HF versus control because of
increased sensitivity to activation by luminal Ca(2+) and was partially
normalized by reducing agents through restoring luminal Ca(2+) sensitivity
oxidation of control RyR2s enhanced their luminal Ca(2+) sensitivity,
thus reproducing the HF phenotype. These findings suggest that redox
modification contributes to abnormal function of RyR2s in HF, presenting
a potential therapeutic target for treating HF.
%0 Journal Article
%1 Tere_2008_1466
%A Terentyev, Dmitry
%A Gy�rke, Inna
%A Belevych, Andriy E
%A Terentyeva, Radmila
%A Sridhar, Arun
%A Nishijima, Yoshinori
%A de Blanco, Esperanza Carcache
%A Khanna, Savita
%A Sen, Chandan K
%A Cardounel, Arturo J
%A Carnes, Cynthia A
%A Gy�rke, Sandor
%D 2008
%J Circ Res
%K Animal; Animals; Calcium Calcium, Cardiac, Channel, Chronic Disease Disease; Dogs; Failure, Heart Models, Myocytes, Oxidation-Reduction; Oxidative Oxygen Post-Translational, Processing, Protein Reactive Receptor Release Reticulum, Ryanodine Sarcoplasmic Species, Stress, adverse effects/metabolism; etiology/metabolism/pathology; metabolism/pathology metabolism/pathology; metabolism; physiology;
%N 12
%P 1466--1472
%R 10.1161/CIRCRESAHA.108.184457
%T Redox modification of ryanodine receptors contributes to sarcoplasmic
reticulum Ca2+ leak in chronic heart failure.
%U http://dx.doi.org/10.1161/CIRCRESAHA.108.184457
%V 103
%X Abnormal cardiac ryanodine receptor (RyR2) function is recognized
as an important factor in the pathogenesis of heart failure (HF).
However, the specific molecular causes underlying RyR2 defects in
HF remain poorly understood. In the present study, we used a canine
model of chronic HF to test the hypothesis that the HF-related alterations
in RyR2 function are caused by posttranslational modification by
reactive oxygen species generated in the failing heart. Experimental
approaches included imaging of cytosolic (Ca(2+)(c)) and sarcoplasmic
reticulum (SR) luminal Ca(2+) (Ca(2+)SR) in isolated intact and
permeabilized ventricular myocytes and single RyR2 channel recording
using the planar lipid bilayer technique. The ratio of reduced to
oxidized glutathione, as well as the level of free thiols on RyR2
decreased markedly in failing versus control hearts consistent with
increased oxidative stress in HF. RyR2-mediated SR Ca(2+) leak was
significantly enhanced in permeabilized myocytes, resulting in reduced
Ca(2+)(SR) in HF compared to control cells. Both SR Ca(2+) leak
and Ca(2+)(SR) were partially normalized by treating HF myocytes
with reducing agents. Conversely, oxidizing agents accelerated SR
Ca(2+) leak and decreased Ca(2+)(SR) in cells from normal hearts.
Moreover, exposure to antioxidants significantly improved intracellular
Ca(2+)-handling parameters in intact HF myocytes. Single RyR2 channel
activity was significantly higher in HF versus control because of
increased sensitivity to activation by luminal Ca(2+) and was partially
normalized by reducing agents through restoring luminal Ca(2+) sensitivity
oxidation of control RyR2s enhanced their luminal Ca(2+) sensitivity,
thus reproducing the HF phenotype. These findings suggest that redox
modification contributes to abnormal function of RyR2s in HF, presenting
a potential therapeutic target for treating HF.
@article{Tere_2008_1466,
abstract = {Abnormal cardiac ryanodine receptor (RyR2) function is recognized
as an important factor in the pathogenesis of heart failure (HF).
However, the specific molecular causes underlying RyR2 defects in
HF remain poorly understood. In the present study, we used a canine
model of chronic HF to test the hypothesis that the HF-related alterations
in RyR2 function are caused by posttranslational modification by
reactive oxygen species generated in the failing heart. Experimental
approaches included imaging of cytosolic ([Ca(2+)](c)) and sarcoplasmic
reticulum (SR) luminal Ca(2+) ([Ca(2+)]SR) in isolated intact and
permeabilized ventricular myocytes and single RyR2 channel recording
using the planar lipid bilayer technique. The ratio of reduced to
oxidized glutathione, as well as the level of free thiols on RyR2
decreased markedly in failing versus control hearts consistent with
increased oxidative stress in HF. RyR2-mediated SR Ca(2+) leak was
significantly enhanced in permeabilized myocytes, resulting in reduced
[Ca(2+)](SR) in HF compared to control cells. Both SR Ca(2+) leak
and [Ca(2+)](SR) were partially normalized by treating HF myocytes
with reducing agents. Conversely, oxidizing agents accelerated SR
Ca(2+) leak and decreased [Ca(2+)](SR) in cells from normal hearts.
Moreover, exposure to antioxidants significantly improved intracellular
Ca(2+)-handling parameters in intact HF myocytes. Single RyR2 channel
activity was significantly higher in HF versus control because of
increased sensitivity to activation by luminal Ca(2+) and was partially
normalized by reducing agents through restoring luminal Ca(2+) sensitivity
oxidation of control RyR2s enhanced their luminal Ca(2+) sensitivity,
thus reproducing the HF phenotype. These findings suggest that redox
modification contributes to abnormal function of RyR2s in HF, presenting
a potential therapeutic target for treating HF.},
added-at = {2009-06-03T11:20:58.000+0200},
author = {Terentyev, Dmitry and Gy�rke, Inna and Belevych, Andriy E and Terentyeva, Radmila and Sridhar, Arun and Nishijima, Yoshinori and de Blanco, Esperanza Carcache and Khanna, Savita and Sen, Chandan K and Cardounel, Arturo J and Carnes, Cynthia A and Gy�rke, Sandor},
biburl = {https://www.bibsonomy.org/bibtex/212c5d6dd9b7b18f6dc37fc02d317a2f2/hake},
description = {The whole bibliography file I use.},
doi = {10.1161/CIRCRESAHA.108.184457},
institution = {Departments of Physiology and Cell Biology, College of Medicine,
Ohio State University, Columbus, OH, USA.},
interhash = {d1fb7b0c650f9809655de31fc3179c79},
intrahash = {12c5d6dd9b7b18f6dc37fc02d317a2f2},
journal = {Circ Res},
keywords = {Animal; Animals; Calcium Calcium, Cardiac, Channel, Chronic Disease Disease; Dogs; Failure, Heart Models, Myocytes, Oxidation-Reduction; Oxidative Oxygen Post-Translational, Processing, Protein Reactive Receptor Release Reticulum, Ryanodine Sarcoplasmic Species, Stress, adverse effects/metabolism; etiology/metabolism/pathology; metabolism/pathology metabolism/pathology; metabolism; physiology;},
month = Dec,
number = 12,
pages = {1466--1472},
pii = {CIRCRESAHA.108.184457},
pmid = {19008475},
timestamp = {2009-06-03T11:21:34.000+0200},
title = {Redox modification of ryanodine receptors contributes to sarcoplasmic
reticulum Ca2+ leak in chronic heart failure.},
url = {http://dx.doi.org/10.1161/CIRCRESAHA.108.184457},
volume = 103,
year = 2008
}