Angiotensin II induces Nox 2- dependent arrhythmias in ventricular cardiomyocytes of mice

Heart failure and cardiac arrhythmias are prevalent diseases which occure mainly in older patients. With regard to the demographic change their importance will even increase in the nexts decades. Mechanisms of heart failure and the developement of arrhythmia are not fully understood yet. The aim of this study is to analyze the role of angiotensin II, NADPH-Oxidase II (Nox2) and CaMKII in this context. Therefore we used two mouse models: CaMKIIδ-Knockout-Mice and gp91phox-Knockout-Mice, both were compared to their wild type. In isolated cardiomyocytes of these mice, we measured action potentials using patch-clamp-technic in whole-cell-configuration and current-clamp-mode. The measurements were performed a) without any pharmacologic intervention b) by adding angiotensin II and c) by adding angiotensin II and DPI (a Nox-2-inhibitor). Our results show that angiotensin increases peak Na current during the action potential. This effect was absent in myocytes lacking functional Nox2 (gp91phox(-/-)). In contrast, genetic knockout of CaMKIIδ (CaMKIIδ(-/-)) did not influence the Ang II-dependent increase in peak INa. Furthermore the results show that Ang II increased the propensity for cellular arrhythmias, for which CaMKII contributes, dependent on Nox2.2015-11-0