Faculty Collaboration Database

Mitochondria oxidative stress, connexin43 remodeling, and sudden arrhythmic death. Circ Arrhythm Electrophysiol 2013 Jun;6(3):623-31

Date

04/06/2013

Pubmed ID

23559673

Pubmed Central ID

PMC3716298

DOI

10.1161/CIRCEP.112.976787

Scopus ID

2-s2.0-84883029046 (requires institutional sign-in at Scopus site)   107 Citations

Abstract

BACKGROUND: Previously, we showed that a mouse model (ACE8/8) of cardiac renin-angiotensin system activation has a high rate of spontaneous ventricular tachycardia and sudden cardiac death secondary to a reduction in connexin43 level. Angiotensin-II activation increases reactive oxygen species (ROS) production, and ACE8/8 mice show increased cardiac ROS. We sought to determine the source of ROS and whether ROS played a role in the arrhythmogenesis.

METHODS AND RESULTS: Wild-type and ACE8/8 mice with and without 2 weeks of treatment with L-NIO (NO synthase inhibitor), sepiapterin (precursor of tetrahydrobiopterin), MitoTEMPO (mitochondria-targeted antioxidant), TEMPOL (a general antioxidant), apocynin (nicotinamide adenine dinucleotide phosphate oxidase inhibitor), allopurinol (xanthine oxidase inhibitor), and ACE8/8 crossed with P67 dominant negative mice to inhibit the nicotinamide adenine dinucleotide phosphate oxidase were studied. Western blotting, detection of mitochondrial ROS by MitoSOX Red, electron microscopy, immunohistochemistry, fluorescent dye diffusion technique for functional assessment of connexin43, telemetry monitoring, and in vivo electrophysiology studies were performed. Treatment with MitoTEMPO reduced sudden cardiac death in ACE8/8 mice (from 74% to 18%; P<0.005), decreased spontaneous ventricular premature beats, decreased ventricular tachycardia inducibility (from 90% to 17%; P<0.05), diminished elevated mitochondrial ROS to the control level, prevented structural damage to mitochondria, resulted in 2.6-fold increase in connexin43 level at the gap junctions, and corrected gap junction conduction. None of the other antioxidant therapies prevented ventricular tachycardia and sudden cardiac death in ACE8/8 mice.

CONCLUSIONS: Mitochondrial oxidative stress plays a central role in angiotensin II-induced gap junction remodeling and arrhythmia. Mitochondria-targeted antioxidants may be effective antiarrhythmic drugs in cases of renin-angiotensin system activation.

Author List

Sovari AA, Rutledge CA, Jeong EM, Dolmatova E, Arasu D, Liu H, Vahdani N, Gu L, Zandieh S, Xiao L, Bonini MG, Duffy HS, Dudley SC Jr

MESH terms used to index this publication - Major topics in bold

Acetophenones
Animals
Antioxidants
Connexin 43
Cyclic N-Oxides
Death, Sudden, Cardiac
Disease Models, Animal
Mice
Mice, Inbred Strains
Mitochondria
NADPH Oxidases
Oxidative Stress
Random Allocation
Reactive Oxygen Species
Renin-Angiotensin System
Risk Factors
Sensitivity and Specificity
Spin Labels
Tachycardia, Ventricular