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(Circulation Research. 2008;103:1466.)
© 2008 American Heart Association, Inc.

Cellular Biology

Redox Modification of Ryanodine Receptors Contributes to Sarcoplasmic Reticulum Ca²⁺ Leak in Chronic Heart Failure

Dmitry Terentyev, Inna Györke, Andriy E. Belevych, Radmila Terentyeva, Arun Sridhar, Yoshinori Nishijima, Esperanza Carcache de Blanco, Savita Khanna, Chandan K. Sen, Arturo J. Cardounel, Cynthia A. Carnes, Sandor Györke

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 College of Pharmacy (A.S., Y.N., E.C.d.B., C.A.C.), Ohio State University, Columbus; and Department of Physiology (A.J.C.), College of Medicine, University of Florida, Gainesville.

Correspondence to Sandor Györke, Davis Heart and Lung Research Institute, Ohio State University Medical Center, 473 W 12th Ave, Columbus, OH 43210. 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 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 because of increased sensitivity to activation by luminal Ca²⁺ and was partially normalized by reducing agents through restoring luminal Ca²⁺ sensitivity oxidation of control RyR2s enhanced their luminal Ca²⁺ 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.

Key Words: ryanodine receptor • heart failure • disulfide oxidation • Ca²⁺-induced Ca²⁺ release

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