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

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.

Short high‐fat diet interferes with the physiological maturation of the late adolescent mouse heart

“…As expected, HFD increased plasma cholesterol levels in HFD compared with chow diet (Figure 1d). However, plasma triglycerides were similar in mice on HFD compared to chow diet (Figure 1d), in line with the previous report (Sanchez et al, 2018).…”

Proarrhythmic Remodeling of Calcium Homeostasis in Cardiac Disease; Implications for Diabetes and Obesity

“…This promoted ventricular ectopy, which was significantly reduced in vivo by a mitochondrial-targeted antioxidant mitoTEMPO. Sánchez et al (2018) reported increased incidences of PVCs and non-sustained VT in HFD-mice vs. controls and this phenomenon was attributed to significantly increased RyR2 oxidation. When antioxidant apocynin was provided in the drinking water, appearance of ventricular arrhythmias in this model was completely abolished.…”

“…A significant increase in mitochondrial oxidative stress was suggested to increase RyR2 oxidation and subsequent SR Ca 2+ release. In 8-week mice with HFD-induced obesity, Sánchez et al (2018) reported a shift in the distribution of single RyR2 channel responsiveness to activating cytosolic [Ca 2+ ], whereby channels were much more active to those isolated from control mice. No changes were observed in RyR2 expression levels or phosphorylation status at S2808 or S2814 sites.…”

“…Alternatively, stabilization could be achieved by a reduction of RyR2 oxidation. In mouse and rat models of type 2 diabetes, it was demonstrated that treatment with ROS scavengers protects against spontaneous Ca 2+ release events, blunting diastolic dysfunction and arrhythmogenesis in vivo ( Shao et al, 2011 ; Joseph et al, 2016 ; Sommese et al, 2016 ; Sánchez et al, 2018 ). Antioxidants may also reduce ROS-dependent CaMKII activation, hence reduce RyR2 phosphorylation and elevated SR Ca 2+ leak ( Luczak and Anderson, 2014 ; Sommese et al, 2016 ; Uchinoumi et al, 2016 ).…”

Mechanisms of Chronic Metabolic Stress in Arrhythmias

“…Further, WT hearts had significantly more inducible ventricular tachycardia than NOX2 KO hearts after HFD. Part of the arrhythmic effect of NOX2 is due to activation of CaMKII, which phosphorylates the RyR2 channels [ 108 , 109 ]. This causes increased calcium leakage from the SR, which worsens mitochondrial function and promotes arrhythmias [ 27 , 77 ].…”