Reducing Oxidative Stress and CaMKII Activity as an Antiarrhythmic Strategy in Woodchucks in Winter

Abstract

Multiple lines of evidence have suggested that increased oxidative stress and activation of Ca2+-calmodulin-dependent protein kinase II (CaMKII) are proarrhythmic in various diseased heart models. In the present study we have evaluated the involvement of oxidative stress and CaMKII pathway in antiarrhythmic mechanisms in a unique coronary artery occlusion (CAO)-induced arrhythmia model in woodchucks. Woodchucks, are true hibernators, and in winter they survive without food or water or activity and their hearts are more resistant to cardiac arrhythmias than in summer. We conducted Western blotting analyses and compared the expression levels of key antioxidant enzymes. In control hearts (without CAO) the expression level of catalase was higher in winter than in summer, while the MnSOD levels were the same. While CAO (24 hrs) upregulated both catalase and MnSOD, the increase in catalase was greater in winter than in summer. Meanwhile, oxidized CaMKII (activated form) levels were lower in winter than in summer. The effects of the CaMKII inhibitor KN-93 on CAO-induced arrhythmias in summer were also evaluated. We carried out CAO surgeries and monitored ECG by telemetry for 24 hrs. KN-93 was administrated with an initial bolus injection followed by a continuous delivery via osmotic minipumps. Arrhythmia scores were evaluated and compared to the control group. KN-93 significantly decreased the arrhythmia score in woodchucks in summer (3.4 ± 0.4) to a lower level (1.3 ± 0.6, p<0.05), which is similar to that observed in winter (1.6 ± 0.3), suggesting the reduction of CaMKII activity may account for the adaptation for the heart's resistance to CAO-induced arrhythmias during winter in woodchucks. These results suggest that manipulation of CaMKII signaling may hold therapeutic potential for treating cardiac arrhythmias.