title: 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 Gα(o1) or Gβ(1)γ(2) 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.
authors.affiliation: Cardiovascular Endocrinology Laboratory, University of Ottawa Heart Institute, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Monica Forero
authors.initials: MF
authors.lastname: McGrath
authors.forename: Tsuneo
authors.initials: T
authors.lastname: Ogawa
authors.forename: Adolfo J
authors.initials: AJ
authors.lastname: de Bold
mesh_terms: D000818:Animals; D009320:Atrial Natriuretic Factor / Q000378:metabolism*; D006332:Cardiomegaly / Q000378:metabolism* / Q000473:pathology; D002460:Cell Line; D002478:Cells, Cultured; D019204:GTP-Binding Proteins / Q000378:metabolism; D020869:Gene Expression Profiling; D066298:In Vitro Techniques; D008297:Male; D023421:Models, Animal; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D020097:Natriuretic Peptide, Brain / Q000378:metabolism*; D034622:RNA Interference; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology; D018631:ras Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: C528215:Rasd1 protein, rat; D020097:Natriuretic Peptide, Brain; D009320:Atrial Natriuretic Factor; D019204:GTP-Binding Proteins; D018631:ras Proteins