Flotillins in the intercalated disc are potential modulators of cardiac excitability.

Autor: Kessler EL; Department of Medical Physiology, Division of Heart & Lungs, University Medical Center Utrecht, Utrecht, the Netherlands. Electronic address: e.l.kessler@umcutrecht.nl., van Stuijvenberg L; Department of Medical Physiology, Division of Heart & Lungs, University Medical Center Utrecht, Utrecht, the Netherlands., van Bavel JJA; Department of Medical Physiology, Division of Heart & Lungs, University Medical Center Utrecht, Utrecht, the Netherlands., van Bennekom J; Department of Medical Physiology, Division of Heart & Lungs, University Medical Center Utrecht, Utrecht, the Netherlands., Zwartsen A; Dutch Poisons Information Center (DPIC), University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands; Neurotoxicology Research Group, Division Toxicology, Institute for Risk Assessment Sciences (IRAS), Faculty of Veterinary Medicine, Utrecht University, Utrecht, the Netherlands., Rivaud MR; Department of Medical Physiology, Division of Heart & Lungs, University Medical Center Utrecht, Utrecht, the Netherlands., Vink A; Department of Pathology, University Medical Center Utrecht, Utrecht, the Netherlands., Efimov IR; Department of Biomedical Engineering, George Washington University, Washington, DC, USA., Postma AV; Department of Clinical Genetics, Amsterdam University Medical Center, Location AMC, the Netherlands., van Tintelen JP; Department of Clinical Genetics, Amsterdam University Medical Center, Location AMC, the Netherlands; Department of Genetics, University Medical Center Utrecht, Utrecht, the Netherlands., Remme CA; Department of Clinical and Experimental Cardiology, Academic Medical Center, University of Amsterdam, the Netherlands., Vos MA; Department of Medical Physiology, Division of Heart & Lungs, University Medical Center Utrecht, Utrecht, the Netherlands., Banning A; Institute of Biochemistry, Medical Faculty, University of Giessen, Germany., de Boer TP; Department of Medical Physiology, Division of Heart & Lungs, University Medical Center Utrecht, Utrecht, the Netherlands., Tikkanen R; Institute of Biochemistry, Medical Faculty, University of Giessen, Germany., van Veen TAB; Department of Medical Physiology, Division of Heart & Lungs, University Medical Center Utrecht, Utrecht, the Netherlands.
Jazyk: angličtina
Zdroj: Journal of molecular and cellular cardiology [J Mol Cell Cardiol] 2019 Jan; Vol. 126, pp. 86-95. Date of Electronic Publication: 2018 Nov 17.
DOI: 10.1016/j.yjmcc.2018.11.007
Abstrakt: 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.
(Copyright © 2018 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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