Reference : The tumour suppressor Ras-association domain family protein 1A (RASSF1A) regulates TN...
Scientific journals : Article
Human health sciences : Cardiovascular & respiratory systems
http://hdl.handle.net/10993/27639
The tumour suppressor Ras-association domain family protein 1A (RASSF1A) regulates TNF-alpha signalling in cardiomyocytes.
English
Mohamed, Tamer M. A. [> >]
Zi, Min [> >]
Prehar, Sukhpal [> >]
Maqsood, Arfa [> >]
Abou-Leisa, Riham [> >]
Nguyen, Loan [> >]
Pfeifer, Gerd P. [> >]
Cartwright, Elizabeth J. [> >]
Neyses, Ludwig mailto [University of Luxembourg > Rectorate > Research Service]
Oceandy, Delvac [> >]
2014
Cardiovascular research
103
1
47-59
Yes (verified by ORBilu)
0008-6363
1755-3245
England
[en] Animals ; Calcium Signaling ; Mice ; Mice, Knockout ; Myocardial Contraction/physiology ; Myocytes, Cardiac/metabolism ; NF-kappa B/metabolism ; Peptide Fragments/chemistry/genetics/metabolism ; Rats ; Rats, Sprague-Dawley ; Receptors, Tumor Necrosis Factor/metabolism ; Sequence Deletion ; Signal Transduction ; TNF Receptor-Associated Death Domain Protein/metabolism ; TNF Receptor-Associated Factor 2/metabolism ; Tumor Necrosis Factor-alpha/metabolism ; Tumor Suppressor Proteins/deficiency/genetics/metabolism ; Calcium transient ; Contractile function ; RASSF1A ; Signal transduction ; Tumour necrosis factor alpha
[en] AIMS: Tumour necrosis factor-alpha (TNF-alpha) plays a key role in the regulation of cardiac contractility. Although cardiomyocytes are known to express the TNF-alpha receptors (TNFRs), the mechanism of TNF-alpha signal transmission is incompletely understood. The aim of this study was to investigate whether the tumour suppressor Ras-association domain family protein 1 isoform A (RASSF1A) modulates TNF-alpha signalling in cardiomyocytes. METHODS AND RESULTS: We used RASSF1A knockout (RASSF1A(-/-)) mice and wild-type (WT) littermates in this study. Acute stimulation with a low dose of TNF-alpha (10 microg/kg iv) increased cardiac contractility and intracellular calcium transients' amplitude in WT mice. In contrast, RASSF1A(-/-) mice showed a blunted contractile response. Mechanistically, RASSF1A was essential in the formation of the TNFR complex (TNFRC), where it functions as an adaptor molecule to facilitate the recruitment of TNFR type 1-associated death domain protein and TNFR-associated factor 2 to form the TNF-alpha receptor complex. In the absence of RASSF1A, signal transmission from the TNF-alpha receptor complex to the downstream effectors, such as cytoplasmic phospholipase A2 and protein kinase A, was attenuated leading to the reduction in the activation of calcium handling molecules, such as L-type Ca(2+) channel and ryanodine receptors. CONCLUSION: Our data indicate an essential role of RASSF1A in regulating TNF-alpha signalling in cardiomyocytes, with RASSF1A being key in the formation of the TNFRC and in signal transmission to the downstream targets.
http://hdl.handle.net/10993/27639
Published on behalf of the European Society of Cardiology. All rights reserved. (c) The Author 2014. For permissions please email: journals.permissions@oup.com.

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