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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 language | English |
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Pages (from-to) | 47-59 |
Number of pages | 12 |
Journal | Cardiovascular research |
Volume | 103 |
Issue number | 1 |
DOIs | |
Publication status | Published - 1 Jul 2014 |
Keywords
- Calcium transient
- Contractile function
- RASSF1A
- Signal transduction
- Tumour necrosis factor alpha
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Dive into the research topics of 'The tumour suppressor Ras-association domain family protein 1A (RASSF1A) regulates TNF-α signalling in cardiomyocytes'. Together they form a unique fingerprint.Projects
- 2 Finished
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The Protective Role of Interleukin-10 Receptor Signalling in the Heart.
Oceandy, D. (PI), Muller, W. (CoI) & Neyses, L. (CoI)
1/09/11 → 28/02/14
Project: Research
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The Role of RASSF1A (Ras Association Domain Family Protein 1A) and Mst2 (Mammalian Sterile 20-Like 2) Signalling Network in Myocardial Hypertrophy.
Oceandy, D. (PI) & Neyses, L. (CoI)
1/04/10 → 31/03/15
Project: Research