Angiotensin II-mediated oxidative stress increased the vulnerability of ventricular arrhythmia in cardiac hypertrophy rabbit model, which is suppressed by CaMKII inhibitor

Abstract Objectives Angiotensin system is a major cause of heart failure and arrhythmia. Despite a lack of direct evidence that oxidative stress causes ventricular arrhythmia, reversal of oxidative stress is considered a plausible therapy. This study evaluated the Ca2+/calmodulin-dependent protein kinase II (CaMKII) inhibitor could suppress arrhythmia in cardiac hypertrophy rabbit model. Methods Angiotensin II (Ang II) or saline was administrated for 2 weeks via osmotic minipumps implanted subcutaneously in the midclavicular region. Hearts were perfused, mapped optically to analyze action potential durations (APD), and restitution kinetics, and tested for VF vulnerability. The intracellular calcium dynamics were measured in cardiomyocyte treated with Ang II (10 ng/ml) for 1 hours. Results In Ang II rabbit groups, 2(30%) rabbits died and had ventricular arrhythmia and hearts had enlarged left ventricle, longer APD90, slower conduction velocity (CV; P<0.01 versus control) and higher levels of transcripts for CaMKII, PLB, RyR2 (P<0.05 versus control). N-acetylcysteine treatment reversed the transcripts for APD90 and CV (P<0.01). Programmed stimulation triggered VF in Ang II (n=5/6) and Ang II + saline (n=4/6), but not in control (n=0/10, P<0.01). Cardiomyocyte induced with Ang II showed increased spontaneous Ca2+ release (Ca2+ Wave Frequency; 1.0±0.0 vs. 5.1±0.5, p=0.001, Ca2+ Amplitude; 1.0±0.0 vs. 1.3±0.1, p=0.001) with control. CaMKII inhibitor reversed the change of Ca2+. Conclusion The Ang II group had an increased incidence of arrhythmia caused by increased phosphorylation of Ca2+ handling proteins. These changes were partially reversed by CaMKII inhibition.