215 REGULATION OF THE TNF-ALPHA SIGNALLING IN CARDIOMYOCYTES BY TUMOR SUPPRESSOR RAS-ASSOCIATION DOMAIN FAMILY PROTEIN 1A (RASSF1A)

Abstract

Introduction 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 signalling, 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 (10 µg/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/µL), 3.3±0.5; Ees after TNF-α stimulation, 5.7±0.8, P Conclusion Our data indicates an essential role of RASSF1A in regulating TNF-α signalling in cardiomyocytes, with RASSF1A being key in the formation of the TNF receptor complex and in signal transmission to the downstream targets. 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.