Increased Energy Demand during Adrenergic Receptor Stimulation Contributes to Ca(2+) Wave Generation Journal Article

Authors: Bovo, E; Mazurek, S. R.; de Tombe, P. P.; Zima, A. V.
Article Title: Increased Energy Demand during Adrenergic Receptor Stimulation Contributes to Ca(2+) Wave Generation
Abstract: While beta-adrenergic receptor (beta-AR) stimulation ensures adequate cardiac output during stress, it can also trigger life-threatening cardiac arrhythmias. We have previously shown that proarrhythmic Ca(2+) waves during beta-AR stimulation temporally coincide with augmentation of reactive oxygen species (ROS) production. In this study, we tested the hypothesis that increased energy demand during beta-AR stimulation plays an important role in mitochondrial ROS production and Ca(2+)-wave generation in rabbit ventricular myocytes. We found that beta-AR stimulation with isoproterenol (0.1 muM) decreased the mitochondrial redox potential and the ratio of reduced to oxidated glutathione. As a result, beta-AR stimulation increased mitochondrial ROS production. These metabolic changes induced by isoproterenol were associated with increased sarcoplasmic reticulum (SR) Ca(2+) leak and frequent diastolic Ca(2+) waves. Inhibition of cell contraction with the myosin ATPase inhibitor blebbistatin attenuated oxidative stress as well as spontaneous SR Ca(2+) release events during beta-AR stimulation. Furthermore, we found that oxidative stress induced by beta-AR stimulation caused the formation of disulfide bonds between two ryanodine receptor (RyR) subunits, referred to as intersubunit cross-linking. Preventing RyR cross-linking with N-ethylmaleimide decreased the propensity of Ca(2+) waves induced by beta-AR stimulation. These data suggest that increased energy demand during sustained beta-AR stimulation weakens mitochondrial antioxidant defense, causing ROS release into the cytosol. By inducing RyR intersubunit cross-linking, ROS can increase SR Ca(2+) leak to the critical level that can trigger proarrhythmic Ca(2+) waves.
Journal Title: Biophysical journal
Volume: 109
Issue: 8
ISSN: 1542-0086; 0006-3495
Publisher: Unknown  
Journal Place: United States
Date Published: 2015
Start Page: 1583
End Page: 1591
Language: eng
Notes: LR: 20151120; CI: Copyright (c) 2015; JID: 0370626; OID: NLM: PMC4624344 [Available on 10/20/16]; PMCR: 2016/10/20 00:00; 2015/04/10 [received]; 2015/08/21 [revised]; 2015/09/01 [accepted]; ppublish