Reversible redox modifications of ryanodine receptor ameliorate ventricular arrhythmias in the ischemic-reperfused heart

Abstract

Previous results from our laboratory showed that phosphorylation of ryanodine receptor 2 (RyR2) by Ca(2+) calmodulin-dependent kinase II (CaMKII) was a critical but not the unique event responsible for the production of reperfusion-induced arrhythmogenesis, suggesting the existence of other mechanisms cooperating in an additive way to produce these rhythm alterations. Oxidative stress is a prominent feature of ischemia/reperfusion injury. Both CaMKII and RyR2 are proteins susceptible to alteration by redox modifications. This study was designed to elucidate whether CaMKII and RyR2 redox changes occur during reperfusion and whether these changes are involved in the genesis of arrhythmias. Langendorff-perfused hearts from rats or transgenic mice with genetic ablation of CaMKII phosphorylation site on RyR2 (S2814A) were subjected to ischemia-reperfusion in the presence or absence of a free radical scavenger (mercaptopropionylglycine, MPG) or inhibitors of NADPH oxidase and nitric oxide synthase. Left ventricular contractile parameters and monophasic action potentials were recorded. Oxidation and phosphorylation of CaMKII and RyR2 were assessed. Increased oxidation of CaMKII during reperfusion had no consequences on the level of RyR2 phosphorylation. Avoiding the reperfusion-induced thiol oxidation of RyR2 with MPG produced a reduction in the number of arrhythmias and did not modify the contractile recovery. Conversely, selective prevention of S-nitrosylation and S-glutathionylation of RyR2 was associated with higher numbers of arrhythmias and impaired contractility. In S2814A mice, treatment with MPG further reduced the incidence of arrhythmias. Taken together, the results suggest that redox modification of RyR2 synergistically with CaMKII phosphorylation modulates reperfusion arrhythmias.

Simvastatin activates single skeletal RyR1 channels but exerts more complex regulation of the cardiac RyR2 isoform

“…For example, statins can alleviate the arrhythmogenic impact of ischaemia/reperfusion by restoration of myocardial perfusion through regression of atheroma (Carnicka et al, ; Birnbaum et al, ), increased NO bioavailability and inhibition of platelet aggregation (Tousoulis et al, ). Ischaemia‐reperfusion has also been linked to redox modifications of RyR2, and it is possible that interaction with a statin reduces oxidative damage (Becerra et al, ).…”

High-Fat-Diet-Induced Obesity Produces Spontaneous Ventricular Arrhythmias and Increases the Activity of Ryanodine Receptors in Mice

“…Likewise, S -nitrosylation also increases RyR2 activity [ 39 ]. Both RyR2 modifications, S -glutathionylation and S -nitrosylation, increase during reperfusion of ischemic hearts, and selective inhibition of any of them further increases the frequency of reperfusion arrhythmias [ 40 ], suggesting a protective effect against arrhythmias in the acute setting of ischemia-reperfusion. Therefore, it is unlikely that S -glutathionylation or S -nitrosylation of RyR2 are responsible for the generation of arrhythmias in this study.…”

Guidelines for experimental models of myocardial ischemia and infarction

“…Although timely reperfusion is essential to salvage viable cardiomyocytes from ischemic death, extensive preclinical and clinical evidence suggests that reperfusion itself causes injury ( 119 , 121 , 147 ). Reperfusion-induced arrhythmias and myocardial stunning are self-limited and reversible forms of reperfusion injury, while microvascular obstruction and lethal cardiomyocyte injury are irreversible and extend damage, thus contributing to adverse outcomes following MI ( 13 , 126 , 177 , 241 , 318 ). In patients, no reflow during reperfusion may be exacerbated due to the generation of microemboli composed of atherosclerotic debris and thrombi during percutaneous coronary interventions ( 135 , 253 ).…”