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

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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.


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.


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.


Our results demonstrated an adverse effect of metabolic components on cardiac electrophysiology and implicated an important role of CaMKII underlying this process.

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