PMID- 30452906
OWN - NLM
STAT- MEDLINE
DCOM- 20200109
LR  - 20200109
IS  - 1095-8584 (Electronic)
IS  - 0022-2828 (Linking)
VI  - 126
DP  - 2019 Jan
TI  - Flotillins in the intercalated disc are potential modulators of cardiac 
      excitability.
PG  - 86-95
LID - S0022-2828(18)30540-6 [pii]
LID - 10.1016/j.yjmcc.2018.11.007 [doi]
AB  - 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.
CI  - Copyright (c) 2018 Elsevier Ltd. All rights reserved.
FAU - Kessler, Elise L
AU  - Kessler EL
AD  - Department of Medical Physiology, Division of Heart & Lungs, University Medical 
      Center Utrecht, Utrecht, the Netherlands. Electronic address: 
      e.l.kessler@umcutrecht.nl.
FAU - van Stuijvenberg, Leonie
AU  - van Stuijvenberg L
AD  - Department of Medical Physiology, Division of Heart & Lungs, University Medical 
      Center Utrecht, Utrecht, the Netherlands.
FAU - van Bavel, Joanne J A
AU  - van Bavel JJA
AD  - Department of Medical Physiology, Division of Heart & Lungs, University Medical 
      Center Utrecht, Utrecht, the Netherlands.
FAU - van Bennekom, Joelle
AU  - van Bennekom J
AD  - Department of Medical Physiology, Division of Heart & Lungs, University Medical 
      Center Utrecht, Utrecht, the Netherlands.
FAU - Zwartsen, Anne
AU  - Zwartsen A
AD  - 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.
FAU - Rivaud, Mathilde R
AU  - Rivaud MR
AD  - Department of Medical Physiology, Division of Heart & Lungs, University Medical 
      Center Utrecht, Utrecht, the Netherlands.
FAU - Vink, Aryan
AU  - Vink A
AD  - Department of Pathology, University Medical Center Utrecht, Utrecht, the 
      Netherlands.
FAU - Efimov, Igor R
AU  - Efimov IR
AD  - Department of Biomedical Engineering, George Washington University, Washington, 
      DC, USA.
FAU - Postma, Alex V
AU  - Postma AV
AD  - Department of Clinical Genetics, Amsterdam University Medical Center, Location 
      AMC, the Netherlands.
FAU - van Tintelen, J Peter
AU  - van Tintelen JP
AD  - Department of Clinical Genetics, Amsterdam University Medical Center, Location 
      AMC, the Netherlands; Department of Genetics, University Medical Center Utrecht, 
      Utrecht, the Netherlands.
FAU - Remme, Carol A
AU  - Remme CA
AD  - Department of Clinical and Experimental Cardiology, Academic Medical Center, 
      University of Amsterdam, the Netherlands.
FAU - Vos, Marc A
AU  - Vos MA
AD  - Department of Medical Physiology, Division of Heart & Lungs, University Medical 
      Center Utrecht, Utrecht, the Netherlands.
FAU - Banning, Antje
AU  - Banning A
AD  - Institute of Biochemistry, Medical Faculty, University of Giessen, Germany.
FAU - de Boer, Teun P
AU  - de Boer TP
AD  - Department of Medical Physiology, Division of Heart & Lungs, University Medical 
      Center Utrecht, Utrecht, the Netherlands.
FAU - Tikkanen, Ritva
AU  - Tikkanen R
AD  - Institute of Biochemistry, Medical Faculty, University of Giessen, Germany.
FAU - van Veen, Toon A B
AU  - van Veen TAB
AD  - Department of Medical Physiology, Division of Heart & Lungs, University Medical 
      Center Utrecht, Utrecht, the Netherlands.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20181117
PL  - England
TA  - J Mol Cell Cardiol
JT  - Journal of molecular and cellular cardiology
JID - 0262322
RN  - 0 (Connexin 43)
RN  - 0 (Membrane Proteins)
RN  - 0 (NAV1.5 Voltage-Gated Sodium Channel)
RN  - 0 (flotillins)
SB  - IM
MH  - Animals
MH  - Animals, Newborn
MH  - Connexin 43/metabolism
MH  - Humans
MH  - Ion Channel Gating
MH  - Membrane Proteins/*metabolism
MH  - Mice, Knockout
MH  - Myocardium/*metabolism
MH  - Myocytes, Cardiac/metabolism
MH  - NAV1.5 Voltage-Gated Sodium Channel/metabolism
MH  - Rats, Wistar
OTO - NOTNLM
OT  - Cardiac excitation
OT  - Desmosome
OT  - Flotillin
OT  - Intercalated disc
OT  - Na(V)1.5
OT  - Reggie
EDAT- 2018/11/20 06:00
MHDA- 2020/01/10 06:00
CRDT- 2018/11/20 06:00
PHST- 2018/07/12 00:00 [received]
PHST- 2018/11/12 00:00 [revised]
PHST- 2018/11/13 00:00 [accepted]
PHST- 2018/11/20 06:00 [pubmed]
PHST- 2020/01/10 06:00 [medline]
PHST- 2018/11/20 06:00 [entrez]
AID - S0022-2828(18)30540-6 [pii]
AID - 10.1016/j.yjmcc.2018.11.007 [doi]
PST - ppublish
SO  - J Mol Cell Cardiol. 2019 Jan;126:86-95. doi: 10.1016/j.yjmcc.2018.11.007. Epub 
      2018 Nov 17.