Journal
CARDIOVASCULAR RESEARCH
Volume 103, Issue 1, Pages 47-59Publisher
OXFORD UNIV PRESS
DOI: 10.1093/cvr/cvu111
Keywords
Calcium transient; Contractile function; RASSF1A; Signal transduction; Tumour necrosis factor alpha
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Funding
- British Heart Foundation (BHF) Intermediate Fellowship [FS/09/046/28043]
- BHF [PG/11/23/28801]
- Medical Research Council (MRC) [G0802004]
- MRC [G0802004] Funding Source: UKRI
- British Heart Foundation [FS/09/046/28043, PG/11/23/28801] Funding Source: researchfish
- Medical Research Council [G1002082, G0802004] Funding Source: researchfish
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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. We used RASSF1A knockout (RASSF1A(-/-)) mice and wild-type (WT) littermates in this study. Acute stimulation with a low dose of TNF-alpha (10 A mu g/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 Ca2+ channel and ryanodine receptors. 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.
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