The tumour suppressor Ras-association domain family protein 1A (RASSF1A) regulates TNF-α signalling in cardiomyocytes

Tamer M A Mohamed, Min Zi, Sukhpal Prehar, Arfa Maqsood, Riham Abou-Leisa, Loan Nguyen, Gerd P. Pfeifer, Elizabeth J. Cartwright, Ludwig Neyses, Delvac Oceandy

Research output: Contribution to journalArticlepeer-review

Abstract

Aims Tumour necrosis factor-α (TNF-α) plays a key role in the regulation of cardiac contractility. Although cardiomyocytes are known to express the TNF-α receptors (TNFRs), the mechanism of TNF-α 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-α 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-α (10 μg/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-α receptor complex. In the absence of RASSF1A, signal transmission from the TNF-α 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 Ca2+ channel and ryanodine receptors. Conclusion Our data indicate an essential role of RASSF1A in regulating TNF-α signalling in cardiomyocytes, with RASSF1A being key in the formation of the TNFRC and in signal transmission to the downstream targets. © 2014 Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014.
Original languageEnglish
Pages (from-to)47-59
Number of pages12
JournalCardiovascular research
Volume103
Issue number1
DOIs
Publication statusPublished - 1 Jul 2014

Keywords

  • Calcium transient
  • Contractile function
  • RASSF1A
  • Signal transduction
  • Tumour necrosis factor alpha

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