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Introduction: Angiotensin II activation and associated elevation in ROS have been implicated in pathogenesis of arrhythmia. We created a transgenic mouse model of cardiac restricted overexpression of ACE (ACE8/8). These mice show spontaneous VT/ VF, SCD, and a reduction in Cx43 level, which impairs conduction and predisposes to arrhythmia. We sought to determine the role and the major source of ROS by angiotensin II in VT/ VF and Cx43 remodeling.Method: Wild type and ACE8/8 mice with and without 2 weeks of treatment with LNIO (NOS inhibitor), Sepiapterin (precursor of BH4), Mito-TEMPO (mitochondria-targeted antioxidant), Apocynin (NADPH oxidase inhibitor), Allopurinol (Xanthine oxidase inhibitor), and ACE8/8 crossed with P67DN were studied. Western blotting, detection of mitochondrial ROS by MitoSOX red, electron microscopy, immunohistochemistry staining, and a fluorescent dye diffusion technique for functional assessment of Cx43 were performed. EP study was performed by a 1.1F catheter through pacing the right ventricle.Results: Treatment with Mito-TEMPO prevented SCD in ACE8/8 mice (p=0.0005, 95% CI of 1.96 to 11.53). Treatment with Mito-TEMPO was also associated with reduction in VT inducibility (from 87% to 50%), correction of gap junction dye conduction (from 75% of control to normal, P |
