Document Detail

Mitochondria Oxidative Stress, Connexin43 Remodeling, and Sudden Arrhythmic Death.
MedLine Citation:
PMID:  23559673     Owner:  NLM     Status:  Publisher    
BACKGROUND: -Previously, we showed a mouse model (ACE8/8) of cardiac renin-angiotensin system (RAS) activation has a high rate of spontaneous ventricular tachycardia (VT) and sudden cardiac death (SCD) secondary to a reduction in connexin43 (Cx43) 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 if ROS played a role in the arrhythmogenesis. METHODS AND RESULTS: -Wild-type and ACE8/8 mice with and without two weeks of treatment with L-NIO (nitric oxide synthase inhibitor), sepiapterin (precursor of tetrahydrobiopterin), MitoTEMPO (mitochondria-targeted antioxidant), TEMPOL (a general antioxidant), apocynin (NADPH oxidase inhibitor), allopurinol (xanthine oxidase inhibitor), and ACE8/8 crossed with P67 dominant negative mice to inhibit the NADPH oxidase were studied. Western blotting, detection of mitochondrial ROS by MitoSOX Red, electron microscopy, immunohistochemistry, fluorescent dye diffusion technique for functional assessment of Cx43, telemetry monitoring, and in-vivo electrophysiology studies were performed. Treatment with MitoTEMPO reduced SCD in ACE8/8 mice (from 74% to 18%, P<0.005), decreased spontaneous ventricular premature beats, decreased VT 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 Cx43 level at the gap junctions, and corrected gap junction conduction. None of the other antioxidant therapies prevented VT and SCD 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 RAS activation.
Ali A Sovari; Cody A Rutledge; Euy-Myoung Jeong; Elena Dolmatova; Divya Arasu; Hong Liu; Nooshin Vahdani; Lianzhi Gu; Shadi Zandieh; Lei Xiao; Marcelo G Bonini; Heather S Duffy; Samuel C Dudley
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2013-4-4
Journal Detail:
Title:  Circulation. Arrhythmia and electrophysiology     Volume:  -     ISSN:  1941-3084     ISO Abbreviation:  Circ Arrhythm Electrophysiol     Publication Date:  2013 Apr 
Date Detail:
Created Date:  2013-4-5     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101474365     Medline TA:  Circ Arrhythm Electrophysiol     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
1University of Illinois at Chicago, Chicago, IL.
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