CaMKII Activation Promotes Cardiac Electrical Remodeling and Increases the Susceptibility to Arrhythmia Induction in High-fat Diet–Fed Mice With Hyperlipidemia Conditions. Issue 4 (October 2017)

• Record Type: Journal Article
• Authors: Zhong, Peng; Quan, Dajun; Huang, Yan; Huang, He
• Is Part Of: Journal of cardiovascular pharmacology. Volume 70:Issue 4(2017)
• Publication Date: 2017-10
• Subjects: CaMKII -- high-fat diet -- hyperlipidemia -- arrhythmias -- Ca2+ handling; Cardiovascular Diseases -- drug therapy -- Periodicals; Cardiovascular System -- drug effects -- Periodicals; Cardiovascular pharmacology -- Periodicals; Cardiovascular agents -- Periodicals; Cardiovascular agents; Cardiovascular pharmacology; Periodicals; 615.7105
• DOI: 10.1097/FJC.0000000000000512
• Languages: English
• ISSNs: 0160-2446

Abstract

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, Ca 2+ 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 Ca 2+ 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.