CaMKII Activation Promotes Cardiac Electrical Remodeling and Increases the Susceptibility to Arrhythmia Induction in High-fat Diet-Fed Mice With Hyperlipidemia Conditions.

Abstract

Background:Obesity/hyperlipidemia is closely related to both atrial and ventricular arrhythmias. CaMKII, a multifunctional serine/threonine kinase, has been involved in cardiac arrhythmias of different etiologies. However, its role in obesity/hyperlipidemia-related cardiac arrhythmia is unexplored. The aim of this was to determine the involvement of CaMKII in the process.Methods:Adult male APOE−/− mice were fed a high-fat diet (HFD), administrated with KN93 (10 mg·kg−1·2d−1), a specific inhibitor of CaMKII. Serum lipid and glucose profile, cardiac function, and surface electrocardiogram were determined. Electrophysiological study and epicardial activation mapping were performed in Langendorff-perfused heart. Expression of cardiac ion channels, gap junction proteins, Ca2+ handling proteins, and CaMKII were evaluated, coupled with histological analysis.Results:A hyperlipidemia condition was induced by HFD in the APOE−/− mice, which was associated with increased expression and activity of CaMKII in the hearts. In Langendorff-perfused hearts, HFD-induced heart showed increased arrhythmia inducibility, prolonged action potential duration, and decreased action potential duration alternans thresholds, coupled with slow ventricular conduction, connexin-43 upregulation, and interstitial fibrosis. Downregulation of ion channels including Cav1.2 and Kv4.2/Kv4.3 and disturbed Ca2+ handling proteins were also observed in HFD-induced heart. Interestingly, all these alterations were significantly inhibited by KN93 treatment.Conclusion:Our results demonstrated an adverse effect of metabolic components on cardiac electrophysiology and implicated an important role of CaMKII underlying this process.