Abstract
Ventricular arrhythmias are a common cause of sudden cardiac death, and their occurrence is higher in obese subjects. Abnormal gating of ryanodine receptors (RyR2), the calcium release channels of the sarcoplasmic reticulum, can produce ventricular arrhythmias. Since obesity promotes oxidative stress and RyR2 are redox-sensitive channels, we investigated whether the RyR2 activity was altered in obese mice. Mice fed a high fat diet (HFD) became obese after eight weeks and exhibited a significant increase in the occurrence of ventricular arrhythmias. Single RyR2 channels isolated from the hearts of obese mice were more active in planar bilayers than those isolated from the hearts of the control mice. At the molecular level, RyR2 channels from HFD-fed mice had substantially fewer free thiol residues, suggesting that redox modifications were responsible for the higher activity. Apocynin, provided in the drinking water, completely prevented the appearance of ventricular arrhythmias in HFD-fed mice, and normalized the activity and content of the free thiol residues of the protein. HFD increased the expression of NOX4, an isoform of NADPH oxidase, in the heart. Our results suggest that HFD increases the activity of RyR2 channels via a redox-dependent mechanism, favoring the appearance of ventricular arrhythmias.
Highlights
IntroductionSudden cardiac death (SCD) represents a high proportion of all natural deaths [1]
Sudden cardiac death (SCD) represents a high proportion of all natural deaths [1]. Ventricular arrhythmias, such as ventricular tachycardia and ventricular fibrillation, that interfere with the normal blood pumping activity of the heart, are prevalent causes of SCD, and obese subjects are at a higher risk of SCD than non-obese subjects [2,3,4]
We previously showed that single RyR2 channels isolated from the hearts and brains of rats and rabbits respond to Ca2+ with low, moderate, or high activation, depending on the redox state of the protein [18,19,20]
Summary
Sudden cardiac death (SCD) represents a high proportion of all natural deaths [1]. Ventricular arrhythmias, such as ventricular tachycardia and ventricular fibrillation, that interfere with the normal blood pumping activity of the heart, are prevalent causes of SCD, and obese subjects are at a higher risk of SCD than non-obese subjects [2,3,4]. Cardiac contraction is initiated by an action potential that spreads through the membrane of the cardiomyocytes. The duration and shape of the ventricular action potential depends on the coordinated interplay of multiple outward and inward ionic currents. Abnormal gating of any of the ion channels responsible for these currents, can be involved in the generation of arrhythmias
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