Coxsackievirus B3 modulates cardiac ion channels

• Published in: The FASEB journal 2013-10, Vol.27 (10), p.4108-4121
• Main Authors: Steinke, Katja, Sachse, Frank, Ettischer, Nicole, Strutz‐Seebohm, Nathalie, Henrion, Ulrike, Rohrbeck, Matthias, Klosowski, Rafael, Wolters, Dirk, Brunner, Stefan, Franz, Wolfgang‐Michael, Pott, Lutz, Munoz, Carlos, Kandolf, Reinhard, Schulze‐Bahr, Eric, Lang, Florian, Klingel, Karin, Seebohm, Guiscard
• Format: Article
• Language: English
• Subjects: Animals; arrhythmias; Computer Simulation; Coxsackievirus B3; CVB3; Enterovirus; Enterovirus B, Human - classification; Enterovirus B, Human - physiology; Gene Expression Regulation - physiology; HEK293 Cells; Humans; Ion Channels - metabolism; Mice; Models, Biological; myocarditis; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - virology; Oocytes; Polymorphism, Genetic; Protein Transport - physiology; trafficking; Xenopus
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fj.13-230193

Infections with coxsackieviruses of type B (CVBs), which are known to induce severe forms of acute and chronic myocarditis, are often accompanied by ventricular arrhythmias and sudden cardiac death. The mechanisms underlying the development of virus‐induced, life‐threatening arrhythmias, which are pheno‐typically similar to those observed in patients having functionally impaired cardiac ion channels, remain, however, enigmatic. In the present study, we show, for the first time, modulating time‐dependent effects of CVB3 on the cardiac ion channels KCNQ1, hERG1, and Cav1.2 in heterologous expression. Channel protein abundance in cellular plasma membrane and patterns of their subcellular distribution were altered in infected murine hearts. The antiviral compound AG7088 did not prevent these effects on channels. In silico analyses of infected human myocytes suggest pronounced alterations of electrical and calcium signaling and increased risk of arrhythmogenesis. These modifications are attenuated by the common Asian polymorphism KCNQ1 P448R, a genetic determinant preventing coxsackievirus‐induced effects in vitro. This study provides a previously unknown explanation for the development of arrhythmias in enteroviral myocarditis, which will help to develop therapeutic strategies for arrhythmia treatment.—Steinke, K., Sachse, F., Ettischer, N., Strutz‐Seebohm, N., Henrion, U., Rohrbeck, M., Klosowski, R., Wolters, D., Brunner, S., Franz, W.‐M., Pott, L., Munoz, C., Kandolf, R., SchulzeBahr, E., Lang, F., Klingel, K., Seebohm, G., Coxsackievirus B3 modulates cardiac ion channels. FASEB J. 27, 4108–4121 (2013). www.fasebj.org