This Article Full Text Full Text (PDF) All Versions of this Article: biophysj.107.114546v1 93/11/4083    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Belevych, A. Articles by Györke, S. Search for Related Content PubMed PubMed Citation Articles by Belevych, A. Articles by Györke, S.

Enhanced Ryanodine Receptor-Mediated Calcium Leak Determines Reduced Sarcoplasmic Reticulum Calcium Content in Chronic Canine Heart Failure

Andriy Belevych ^* , Zuzana Kubalova ^¶, Dmitry Terentyev ^* , Robert L. Hamlin , Cynthia A. Carnes ^*  and Sandor Györke ^* 

^* Davis Heart and Lung Research Institute, Department of Physiology and Cell Biology, Department of Veterinary Biosciences, and College of Pharmacy, The Ohio State University Medical Center, Columbus, Ohio 43210; and ^¶ Institute of Molecular Physiology and Genetics, Slovak Academy of Sciences, Bratislava, Slovak Republic

Correspondence: Address reprint requests to Sandor Györke, Davis Heart and Lung Research Institute, The Ohio State University Medical Center, 473 W. 12th Avenue, Columbus, OH 43210. E-Mail: Sandor.Gyorke{at}osumc.edu.

In this study, we investigated the role of elevated sarcoplasmic reticulum (SR) Ca²⁺ leak through ryanodine receptors (RyR2s) in heart failure (HF)-related abnormalities of intracellular Ca²⁺ handling, using a canine model of chronic HF. The cytosolic Ca²⁺ transients were reduced in amplitude and slowed in duration in HF myocytes compared with control, changes paralleled by a dramatic reduction in the total SR Ca²⁺ content. Direct measurements of [Ca²⁺]_SR in both intact and permeabilized cardiac myocytes demonstrated that SR luminal [Ca²⁺] is markedly lowered in HF, suggesting that alterations in Ca²⁺ transport rather than fractional SR volume reduction accounts for the diminished Ca²⁺ release capacity of SR in HF. SR Ca²⁺ ATPase (SERCA2)-mediated SR Ca²⁺ uptake rate was not significantly altered, and Na⁺/Ca²⁺ exchange activity was accelerated in HF myocytes. At the same time, SR Ca²⁺ leak, measured directly as a loss of [Ca²⁺]_SR after inhibition of SERCA2 by thapsigargin, was markedly enhanced in HF myocytes. Moreover, the reduced [Ca²⁺]_SR in HF myocytes could be nearly completely restored by the RyR2 channel blocker ruthenium red. The effects of HF on cytosolic and SR luminal Ca²⁺ signals could be reasonably well mimicked by the RyR2 channel agonist caffeine. Taken together, these results suggest that RyR2-mediated SR Ca²⁺ leak is a major factor in the abnormal intracellular Ca²⁺ handling that critically contributes to the reduced SR Ca²⁺ content of failing cardiomyocytes.

This article has been cited by other articles:

				J. H. B. Bridge and E. Savio Revealing the Cellular Basis of Heart Failure Biophys. J., December 1, 2007; 93(11): 3731 - 3732. [Full Text] [PDF]