Controlled and Cardiac-Restricted Overexpression of the Arginine Vasopressin V1A Receptor Causes Reversible Left Ventricular Dysfunction Through G alpha(q)-Mediated Cell Signaling
ABSTRACT [Arg8]-vasopressin (AVP) activates 3 G-protein-coupled receptors: V1A, V2, and V1B. The AVP-V1A receptor is the primary AVP receptor in the heart; however, its role in cardiac homeostasis is controversial. To better understand AVP-mediated signaling in the heart, we created a transgenic mouse with controlled overexpression of the V1A receptor.
The V1A receptor transgene was placed under the control of the tetracycline-regulated, cardiac-specific α-myosin heavy chain promoter (V1A-TG). V1A-TG mice had a normal cardiac function phenotype at 10 weeks of age; however, by 24 weeks of age, tetracycline-transactivating factor/V1A-TG mouse hearts had reduced cardiac function, cardiac hypertrophy, and dilatation of the ventricular cavity. Contractile dysfunction was also observed in isolated adult cardiac myocytes. When V1A receptor transgene was induced to be expressed in adult mice (V1A-TG(Ind)), left ventricular dysfunction and dilatation were also seen, albeit at a later time point. Because the V1A receptor mediates cell signaling through Gα(q) protein, we blocked Gα(q) signaling by crossing tetracycline-transactivating factor/V1A mice with transgenic mice that expressed a small inhibitory peptide against Gα(q). Gα(q) blockade abrogated the development of the heart failure phenotype in tetracycline-transactivating factor/V1A-TG mice. The heart failure phenotype could be reversed by administration of doxycycline.
Our results demonstrate a role for V1A-mediated signaling in the development of heart failure and support a role for V1A blockade in the treatment of patients with elevated levels of vasopressin.
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ABSTRACT: -Enhanced arginine vasopressin (AVP) levels are associated with increased mortality during end-stage human heart failure (HF), and cardiac AVP type 1A receptor (V1AR) expression becomes increased. Additionally, mice with cardiac-restricted V1AR overexpression develop cardiomyopathy and decreased β-adrenergic receptor (βAR) responsiveness. This led us to hypothesize that V1AR signaling regulated βAR responsiveness and in doing so contributes to HF development.Circulation 09/2014; DOI:10.1161/CIRCULATIONAHA.114.010434 · 14.95 Impact Factor
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ABSTRACT: The central roles of neurohormonal abnormalities in the pathobiology of heart failure have been defined in recent decades. Experiments have revealed both systemic involvement and intricate subcellular regulation by circulating effectors of the sympathetic nervous system, the renin-angiotensin-aldosterone system, and others. Randomized clinical trials substantiated these findings, establishing neurohormonal antagonists as cornerstones of heart failure pharmacotherapy, and occasionally offering further insight on mode of benefit. This review discusses the use of β-blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and aldosterone receptor antagonists in the treatment of heart failure, with particular attention to the pathophysiologic basis and mechanisms of action.Heart Failure Clinics 10/2014; 10(4). DOI:10.1016/j.hfc.2014.07.002 · 1.41 Impact Factor
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ABSTRACT: OBJECTIVE: To understand the biological pathways involved in twin-twin transfusion syndrome (TTTS) by performing global gene expression analysis of amniotic fluid (AF) cell-free RNA. METHODS: Prospective whole transcriptome microarray study analyzing cell-free RNA in AF from TTTS recipient twins and singleton controls. Significantly differentially-regulated genes in TTTS cases (N = 8) vs. matched controls (N = 8) were identified and pathways analyses performed. Significant gene expression differences between Stage II TTTS recipients (N = 5) and Stage III TTTS recipients with abnormal Doppler measurements (N = 5) were also analysed. RESULTS: Analysis of paired data from TTTS cases and controls revealed differential expression of 801 genes, which were significantly enriched for neurological disease and cardiovascular system pathways. We also identified cardiovascular genes and pathways associated with the presence of critically abnormal Doppler measurements in Stage III TTTS recipients. CONCLUSIONS: This study provides the first transcriptome-wide data on the impact of TTTS on fetal development. Our results show that gene expression involving neurological and cardiovascular pathways are altered in recipient fetuses prior to surgical treatment. This has relevance for the origins of long-term complications seen in survivors and for the development of future fetal biomarkers. This article is protected by copyright. All rights reserved.Prenatal Diagnosis 09/2013; 33(9). DOI:10.1002/pd.4150 · 2.51 Impact Factor