Ras dexamethasone-induced protein 1 is a modulator of hormone secretion in the volume overloaded heart

Abstract

Because of the crucial role of the endocrine heart in maintaining homeostasis, considerable effort has been focused on the elucidation of the mechanistic underlying gene expression and secretion of the cardiac hormones atrial natriuretic factor (ANF) and brain natriuretic peptide (BNP). However, much remains to be determined regarding specific molecular events involved in cardiocyte secretory function. In this work, we identified genes involved in the transcriptional response of the endocrine heart to volume overload (VO) and signaling pathways involved in its regulation. To this end, the cardiac atrial and ventricular transcriptomes were analyzed in the heart of rats subjected to experimentally induced aorto-caval shunt VO. Pathway analysis revealed unique gene expression profiles in the VO atria for G-protein signaling, notably a significant downregulation of Ras dexamethasone-induced protein 1 (RASD1). In vitro, knockdown of RASD1 in the atrial-derived HL-1 cells, significantly increased ANF secretion. Concurrent knockdown of RASD1 and its effectors Gαo1 or Gβ1γ2 abrogated the endocrine response, demonstrating a previously unknown negative modulator role for RASD1. RASD1 thus emerges as a tonic inhibitor of ANF secretion and illustrates for the first time the concept of inhibitory protein regulators of ANF release. The novel molecular function identified herein for RASD1 is of considerable importance given its therapeutic implications for cardiovascular disease.

Gene Expression and Proteomic Profiling of Lp (a)-Induced Signalling Pathways in Human Aortic Valve Interstitial Cells

“…RASD1 exerts its action by modulating multiple signalling cascades, and its upregulation in breast [26] and prostate [27] cancer led to increased apoptosis. Moreover, RASD1 expression negatively correlated with cardiac hormone atrial natriuretic factor (ANF) secretion in volume overloaded atria, an effect of stress-induced hypertrophy in CAD, thus contributing to disruption of cardiac hormone homeostasis [28]. Lp (a) is also elevated in CAD, and aortic valve stenosis is known to have many mechanistic similarities with CAD and atherosclerosis.…”

Activators of G Protein Signaling Exhibit Broad Functionality and Define a Distinct Core Signaling Triad

“…Both AGS1 and Rhes have an extended carboxyl terminus as compared with Ras family proteins, and both proteins interact with G i /G o and regulate G protein signaling (Cismowski et al, , 2000Graham et al, 2002Graham et al, , 2004Takesono et al, 2002;Vargiu et al, 2004;Nguyen and Watts, 2005;Harrison and He, 2011). AGS1 has a range of functional roles, including inhibition of cell growth, N-methyl-D-aspartate receptor signaling, regulation of the circadian rhythm, and regulation of hormone secretion (Fang et al, 2000;Graham et al, 2001;Jaffrey et al, 2002;Takahashi et al, 2003;Cheng et al, 2004;Vaidyanathan et al, 2004;Lellis-Santos et al, 2012;McGrath et al, 2012;Chen et al, 2013;Harrison et al, 2013). Rhes …”

The Roles of Rasd1 small G proteins and leptin in the activation of TRPC4 transient receptor potential channels

“…43 Also Rasd1 has a function to regulate neurotransmitter mediated behaviors 44 and cancers. 45 The functional relationship between TRPC4 and small GTPase Rasd1…”