Published online before print November 13, 2008, doi: 10.1161/CIRCRESAHA.108.184457
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Submitted on February 24, 2008
Revised on September 29, 2008
Accepted on October 30, 2008
Redox Modification of Ryanodine Receptors Contributes to Sarcoplasmic Reticulum Ca2+ Leak in Chronic Heart Failure
Dmitry Terentyev ;
From the Departments of Physiology and Cell Biology (D.T., I.G., A.E.B., R.T., C.A.C., S.G.) and Surgery (S.K., C.K.S.), College of Medicine; and Department of Pharmacy and Biophysics (A.S., Y.N., E.C.d.B., C.A.C.), College of Pharmacy, Ohio State University, Columbus; and Department of Physiology (A.J.C.), College of Medicine, University of Florida, Tallahassee.
* To whom correspondence should be addressed. E-mail: Sandor.Gyorke{at}osumc.edu.
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 ([Ca2+]c) and sarcoplasmic reticulum (SR) luminal Ca2+ ([Ca2+]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 Ca2+ leak measured directly as a time-dependent decline in [Ca2+]SR on blocking SR Ca2+ uptake was significantly enhanced in permeabilized myocytes, resulting in reduced [Ca2+]SR in HF compared to control cells. Both SR Ca2+ leak and [Ca2+]SR were partially normalized by treating HF myocytes with reducing agents. Conversely, oxidizing agents accelerated SR Ca2+ leak and decreased [Ca2+]SR in cells from normal hearts. Moreover, exposure to antioxidants significantly improved intracellular Ca2+-handling parameters in intact HF myocytes. Single RyR2 channel activity was significantly higher in HF versus control and was partially normalized by reducing agents, whereas oxidation of control RyR2s enhanced their activity 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.
Key words: ryanodine receptor • heart failure • disulfide oxidation • Ca2+-induced Ca2+ release
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