title: Mitochondria oxidative stress, connexin43 remodeling, and sudden arrhythmic death.
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.
  
  
  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.
authors.affiliation: Section of Cardiology and Center for Cardiovascular Research, University of Illinois at Chicago, IL, USA.
authors.forename: Ali A
authors.initials: AA
authors.lastname: Sovari
authors.forename: Cody A
authors.initials: CA
authors.lastname: Rutledge
authors.forename: Euy-Myoung
authors.initials: EM
authors.lastname: Jeong
authors.forename: Elena
authors.initials: E
authors.lastname: Dolmatova
authors.forename: Divya
authors.initials: D
authors.lastname: Arasu
authors.forename: Hong
authors.initials: H
authors.lastname: Liu
authors.forename: Nooshin
authors.initials: N
authors.lastname: Vahdani
authors.forename: Lianzhi
authors.initials: L
authors.lastname: Gu
authors.forename: Shadi
authors.initials: S
authors.lastname: Zandieh
authors.forename: Lei
authors.initials: L
authors.lastname: Xiao
authors.forename: Marcelo G
authors.initials: MG
authors.lastname: Bonini
authors.forename: Heather S
authors.initials: HS
authors.lastname: Duffy
authors.forename: Samuel C
authors.initials: SC
authors.lastname: Dudley
mesh_terms: D000098:Acetophenones / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D018031:Connexin 43 / Q000187:drug effects / Q000378:metabolism*; D003497:Cyclic N-Oxides / Q000494:pharmacology; D016757:Death, Sudden, Cardiac / Q000209:etiology*; D004195:Disease Models, Animal; D051379:Mice; D008815:Mice, Inbred Strains; D008928:Mitochondria / Q000378:metabolism*; D019255:NADPH Oxidases / Q000494:pharmacology; D018384:Oxidative Stress / Q000502:physiology*; D011897:Random Allocation; D017382:Reactive Oxygen Species / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000187:drug effects; D012307:Risk Factors; D012680:Sensitivity and Specificity; D013113:Spin Labels; D017180:Tachycardia, Ventricular / Q000188:drug therapy* / Q000503:physiopathology
chemical_list: D000098:Acetophenones; D000975:Antioxidants; D018031:Connexin 43; D003497:Cyclic N-Oxides; D017382:Reactive Oxygen Species; D013113:Spin Labels; C056165:acetovanillone; D019255:NADPH Oxidases; C001803:tempol
keywords: mitochondria; oxidative stress; sudden cardiac death; ventricular tachycardia
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