Abstract 15801: 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, sudden cardiac death (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 in angiotensin II mediated VT/ VF and Cx43 remodeling.
Method: Wild type and ACE8/8 mice with and without two weeks of treatment with a NOS inhibitor (L-NIO, 25 mg/Kg IP injections daily), a mitochondria-targeted antioxidant (Mito-TEMPO, 0.7 mg/Kg IP injections daily), and a NADPH oxidase inhibitor (apocynin 80 mg/L in drinking water) were studied. Crossing ACE8/8 mice with a P67 dominant negative (P67DN) mouse was used to confirm the NADPH oxidase role. Western blotting to detect oxidized protein levels (OxyBlot), detection of superoxide production in mitochondria by confocal microscopy and flow cytometry using MitoSOX red, and immunohistochemistry staining for Cx43 were performed. EP study was performed by a 1.1F octapolar catheter and a burst pacing protocol.
Results: Proteins were more oxidized, mitochondrial ROS levels were increased by 6 fold (P < 0.05), and Cx43 was reduced in ACE8/8 to 33% of control (P < 0.05). Treatment with Mito-TEMPO prevented SCD and improved survival in ACE8/8 mice (p=0.0005, 95% CI of 1.96 to 11.53) and reduced mitochondrial ROS level to 1.8 fold of the control (p < 0.05). Inducibility of VT/VF was higher in ACE8/8 mice compare to WT (87.5% vs. 2.3%, P <0.05), 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 and apocynin or crossing with the P67DN mice did not prevent VT/VF and SCD in ACE8/8 mice.
Conclusion: Mitochondria-targeted antioxidant prevents VT/VF/SCD and Cx43 remodeling in an angiotensin II activated state. This result suggests a central role for mitochondria oxidative stress in ROS-induced arrhythmia and that mitochondria-targeted antioxidants may be effective antiarrhythmic drugs.
- © 2011 by American Heart Association, Inc.