Abstract P342: Mitochondria-Targeted Antioxidant Therapy Prevents Angiotensin II--Mediated Connexin43 Remodeling and Sudden Arrhythmic Death
Introduction: Angiotensin II activation and associated elevation in ROS have been implicated in pathogenesis of arrhythmia. Nevertheless commonly used antioxidants have been ineffective in clinical trials. 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 a NOS inhibitor (L-NIO, 25mg/Kg IP injections daily), a mitochondria-targeted antioxidant (Mito-TEMPO, 0.7mg/Kg IP injections daily), a NADPH oxidase inhibitor (Apocynin 80mg/L in drinking water), and ACE8/8 crossed with P67DN were studied. Western blotting (with derivatization to dinitrophenylhydrozone to detect oxidized protein levels), detection of superoxide production in mitochondria by red mitochondrial superoxide indicator and immunohistochemistry staining for Cx43 were performed. EP study was performed by a 1.1F octapolar catheter through pacing the right ventricle using a burst pacing protocol.
Results: Proteins were more oxidized (increased protein-carbonyl detection), and Cx43 was reduced in ACE8/8 to 33% of control. Treatment with Mito-TEMPO prevented SCD and improved survival in ACE8/8 mice (p=0.0005, hazard ratio 4.76 with 95% CI of 1.96 to 11.53). Inducibility of VT/VF was higher in ACE8/8 mice compare to WT (87.5% vs. 2.3%) and VT inducibility was reduced with Mito-TEMPO treatment (50% in treatment group). Cx43 level was increased by 1.7 fold with Mito-TEMPO treatment. Treatments with L-NIO, Apocynin and crossing with P67DN mice did not prevent VT/VF and SCD in ACE8/8 mice.
Conclusion: In a model of angiotensin II activation mitochondria-targeted antioxidant, prevents VT/VF/SCD and Cx43 remodeling. Suppression of NADPH oxidase activity by Apocynin and crossing the ACE8/8 mice with P67DN or inhibition of NOS by L-NIO did not prevent the arrhythmic deaths in ACE8/8 mice. This result suggests that mitochondria are the major source of ROS by angiotensin II and mitochondria-targeted antioxidants may be effective antiarrhythmic drugs.
- © 2011 by American Heart Association, Inc.