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• W2331775315 abstract "Purpose: Tumour necrosis factor-α (TNF-α) is a pro-inflammatory cytokine which plays key roles in the pathogenesis of heart failure. Cardiomyocytes express the TNF-α receptor (TNFR), however, the mechanism of TNF-α signal transmission in cardiomyocytes is not completely understood. Here we show a novel regulator of TNF-α signaling, the Ras-association domain family 1 isoform A (RASSF1A), which regulates cardiac contractility and intracellular calcium through interaction with TNFR1.Methods and results: We used RASSF1A knockout (KO) mice and wild type (WT) controls and stimulated them with TNF-α (10μg/kg i.v.). In WT mice acute treatment with low dose of TNF-α increased cardiac contractility as indicated by the change in end systolic elastance (Ees) (baseline Ees (mmHg/mL), 3.3±0.5; Ees after TNF-α stimulation, 5.7±0.8, P<0.05) which is consistent with previously published data (Circulation 2004; 109:406-411). However, KO mice showed a blunted contractile response following acute TNF-a treatment (baseline Ees: 3.05±0.4 vs Ees after TNF-α: 2.54±0.3). Consistently, isolated cardiomyocytes from WT mice showed 40% increase in calcium transient amplitude in response to TNF-α (10 ng/ml) stimulation (n=24 cells, p<0.05). However, KO cardiomyocytes showed no significant increase in calcium transient amplitude following the same stimulation (n=24 cells). We also found that RASSF1A formed a molecular complex with TNFR1 in cardiomyocytes and this interaction was essential in the recruitment of TRADD and TRAF2, the major downstream effectors of TNF-α signalling. By mapping the interaction domain we found that the C-terminal region of RASSF1A was responsible for the formation of TNF-α receptor complex. Mechanistically, RASSF1A is essential in regulating calcium transients and contractility in cardiomyocytes downstream of TNF-α signaling through regulation of cytoplasmic phospholipase A2 (cPLA2) and phosphorylation of calcium handling molecules. Furthermore, using an adenoviral-mediated shRNA construct we found that cardiomyocytes lacking RASSF1A exhibited reduced activation of NFκB, a downstream target of TNF-α.Conclusion: Our data indicates an essential role of RASSF1A in regulating TNF-α signaling in cardiomyocytes. Moreover, our present work contributes a novel effector pathway via RASSF1A which transmits the positive inotropic effect of TNF-α and should therefore be preserved or even stimulated in the treatment of heart failure. In addition, enhancement of RASSF1A function/expression might well benefit patients with heart failure." @default.
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• W2331775315 date "2013-08-02" @default.
• W2331775315 modified "2023-09-26" @default.
• W2331775315 title "The tumor suppressor RAS-association domain family protein 1A (RASSF1A) regulates TNF-alpha signaling in cardiomyocytes" @default.
• W2331775315 doi "https://doi.org/10.1093/eurheartj/eht307.36" @default.
• W2331775315 hasPublicationYear "2013" @default.
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