Journalartikel

Jahr der Veröffentlichung: 2019

Seiten: 86-95

Zeitschrift: Journal of Molecular and Cellular Cardiology

Bandnummer: 126

ISSN: 0022-2828

eISSN: 1095-8584

DOI Link: https://doi.org/10.1016/j.yjmcc.2018.11.007

Verlag: Elsevier

Abstract: 

Background The intercalated disc (ID) is important for cardiac remodeling and has become a subject of intensive research efforts. However, as yet the composition of the ID has still not been conclusively resolved and the role of many proteins identified in the ID, like Flotillin-2, is often unknown. The Flotillin proteins are known to be involved in the stabilization of cadherins and desmosomes in the epidermis and upon cancer development. However, their role in the heart has so far not been investigated. Therefore, in this study, we aimed at identifying the role of Flotillin-1 and Flotillin-2 in the cardiac ID.

Methods: Location of Flotillins in human and murine cardiac tissue was evaluated by fluorescent immunolabeling and co-immunoprecipitation. In addition, the effect of Flotillin knockout (KO) on proteins of the ID and in electrical excitation and conduction was investigated in cardiac samples of wildtype (WT), Flotillin-1 KO, Flotilin-2 KO and Flotilin-1/2 double KO mice. Consequences of Flotillin knockdown (KD) on cardiac function were studied (patch clamp and Multi Electrode Array (MEA)) in neonatal rat cardiomyocytes (NRCMs) transfected with siRNAs against Flotillin-1 and/or Flotillin-2.

Results: First, we confirmed presence in the ID and mutual binding of Flotillin-1 and Flotillin-2 in murine and human cardiac tissue. Flotillin KO mice did not show cardiac fibrosis, nor hypertrophy or changes in expression of the desmosomal ID proteins. However, protein expression of the cardiac sodium channel Na(v)1.5 was significantly decreased in Flotillin-1 and Flotillin-1/2 KO mice compared to WT mice. In addition, sodium current density showed a significant decrease upon Flotillin-1/2 KD in NRCMs as compared to scrambled siRNA-transfected NRCMs. MEA recordings of Flotillin-2 KD NRCM cultures showed a significantly decreased spike amplitude and a tendency of a reduced spike slope when compared to control and scrambled siRNA-transfected cultures.

Conclusions: In this study, we demonstrate the presence of Flotillin-1, in addition to Flotillin-2 in the cardiac ID. Our findings indicate a modulatory role of Flotillins on Na(v)1.5 expression at the ID, with potential consequences for cardiac excitation.

Harvard-Zitierstil: Kessler, E., van Stuijvenberg, L., van Bavel, J., van Bennekom, J., Zwartsen, A., Rivaud, M., et al. (2019) Flotillins in the intercalated disc are potential modulators of cardiac excitability, Journal of Molecular and Cellular Cardiology, 126, pp. 86-95. https://doi.org/10.1016/j.yjmcc.2018.11.007

APA-Zitierstil: Kessler, E., van Stuijvenberg, L., van Bavel, J., van Bennekom, J., Zwartsen, A., Rivaud, M., Vink, A., Efimov, I., Postma, A., van Tintelen, J., Remme, C., Vos, M., Banning, A., de Boer, T., Tikkanen, R., & van Veen, T. (2019). Flotillins in the intercalated disc are potential modulators of cardiac excitability. Journal of Molecular and Cellular Cardiology. 126, 86-95. https://doi.org/10.1016/j.yjmcc.2018.11.007