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Int. J. Mol. Sci. 2018, 19(2), 533; https://doi.org/10.3390/ijms19020533

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

1
Programa de Fisiopatología, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, 8380453 Santiago, Chile
2
Programa de Fisiología y Biofísica, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, 8380453 Santiago, Chile
3
Escuela de Ciencias Veterinarias, Universidad de Viña del Mar, 2572007 Viña del Mar, Valparaíso, Chile
4
Advanced Center for Chronic Diseases, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, 8380494 Santiago, Chile
5
Instituto de Investigación en Ciencias Odontológicas, Facultad de Odontología, Universidad de Chile, 8380492 Santiago, Chile
6
Centro de Investigaciones Cardiovasculares, CCT-CONICET La Plata, Facultad de Medicina, Universidad Nacional de La Plata, 1900 La Plata, Argentina
These authors contributed equally to this work.
*
Author to whom correspondence should be addressed.
Received: 9 January 2018 / Revised: 26 January 2018 / Accepted: 7 February 2018 / Published: 10 February 2018
(This article belongs to the Special Issue Oxidative Stress in Cardiovascular Disease 2018)
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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. View Full-Text
Keywords: calcium release channels; reactive oxygen species (ROS); redox modifications; ventricular tachycardia; NADPH oxidase calcium release channels; reactive oxygen species (ROS); redox modifications; ventricular tachycardia; NADPH oxidase
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Sánchez, G.; Araneda, F.; Peña, J.P.; Finkelstein, J.P.; Riquelme, J.A.; Montecinos, L.; Barrientos, G.; Llanos, P.; Pedrozo, Z.; Said, M.; Bull, R.; Donoso, P. High-Fat-Diet-Induced Obesity Produces Spontaneous Ventricular Arrhythmias and Increases the Activity of Ryanodine Receptors in Mice. Int. J. Mol. Sci. 2018, 19, 533.

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