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Serotonin 2B Receptor Antagonism Prevents Heritable Pulmonary Arterial Hypertension.
West JD, Carrier EJ, Bloodworth NC, Schroer AK, Chen P, Ryzhova LM, Gladson S, Shay S, Hutcheson JD, Merryman WD
(2016) PLoS One 11: e0148657
MeSH Terms: Animals, Bone Morphogenetic Protein Receptors, Type II, Cell Movement, Cytoskeletal Proteins, Gene Expression Profiling, Gene Expression Regulation, Hypertension, Pulmonary, Indoles, Lung, Mice, Mice, Transgenic, Muscle Contraction, Muscle Proteins, Mutation, Myocytes, Smooth Muscle, Oligonucleotide Array Sequence Analysis, Phosphorylation, Protein Transport, Receptor, Serotonin, 5-HT2B, Serotonin Antagonists, Signal Transduction, Urea, Vascular Stiffness, src-Family Kinases
Show Abstract · Added April 11, 2017
Serotonergic anorexigens are the primary pharmacologic risk factor associated with pulmonary arterial hypertension (PAH), and the resulting PAH is clinically indistinguishable from the heritable form of disease, associated with BMPR2 mutations. Both BMPR2 mutation and agonists to the serotonin receptor HTR2B have been shown to cause activation of SRC tyrosine kinase; conversely, antagonists to HTR2B inhibit SRC trafficking and downstream function. To test the hypothesis that a HTR2B antagonist can prevent BMRP2 mutation induced PAH by restricting aberrant SRC trafficking and downstream activity, we exposed BMPR2 mutant mice, which spontaneously develop PAH, to a HTR2B antagonist, SB204741, to block the SRC activation caused by BMPR2 mutation. SB204741 prevented the development of PAH in BMPR2 mutant mice, reduced recruitment of inflammatory cells to their lungs, and reduced muscularization of their blood vessels. By atomic force microscopy, we determined that BMPR2 mutant mice normally had a doubling of vessel stiffness, which was substantially normalized by HTR2B inhibition. SB204741 reduced SRC phosphorylation and downstream activity in BMPR2 mutant mice. Gene expression arrays indicate that the primary changes were in cytoskeletal and muscle contractility genes. These results were confirmed by gel contraction assays showing that HTR2B inhibition nearly normalizes the 400% increase in gel contraction normally seen in BMPR2 mutant smooth muscle cells. Heritable PAH results from increased SRC activation, cellular contraction, and vascular resistance, but antagonism of HTR2B prevents SRC phosphorylation, downstream activity, and PAH in BMPR2 mutant mice.
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24 MeSH Terms
5-HT(2B) antagonism arrests non-canonical TGF-β1-induced valvular myofibroblast differentiation.
Hutcheson JD, Ryzhova LM, Setola V, Merryman WD
(2012) J Mol Cell Cardiol 53: 707-14
MeSH Terms: Actins, Animals, Aortic Diseases, Aortic Valve, Calcinosis, Cell Differentiation, Cells, Cultured, Gene Expression, Indoles, Microfilament Proteins, Muscle Proteins, Myofibroblasts, Phosphorylation, Plasminogen Activator Inhibitor 1, Promoter Regions, Genetic, Protein Processing, Post-Translational, Protein Transport, Pyridines, Receptor, Serotonin, 5-HT2B, Serotonin 5-HT2 Receptor Antagonists, Signal Transduction, Smad3 Protein, Sus scrofa, Transcriptional Activation, Transforming Growth Factor beta1, Urea, p38 Mitogen-Activated Protein Kinases, src-Family Kinases
Show Abstract · Added February 12, 2015
Transforming growth factor-β1 (TGF-β1) induces myofibroblast activation of quiescent aortic valve interstitial cells (AVICs), a differentiation process implicated in calcific aortic valve disease (CAVD). The ubiquity of TGF-β1 signaling makes it difficult to target in a tissue specific manner; however, the serotonin 2B receptor (5-HT(2B)) is highly localized to cardiopulmonary tissues and agonism of this receptor displays pro-fibrotic effects in a TGF-β1-dependent manner. Therefore, we hypothesized that antagonism of 5-HT(2B) opposes TGF-β1-induced pathologic differentiation of AVICs and may offer a druggable target to prevent CAVD. To test this hypothesis, we assessed the interaction of 5-HT(2B) antagonism with canonical and non-canonical TGF-β1 pathways to inhibit TGF-β1-induced activation of isolated porcine AVICs in vitro. Here we show that AVIC activation and subsequent calcific nodule formation is completely mitigated by 5-HT(2B) antagonism. Interestingly, 5-HT(2B) antagonism does not inhibit canonical TGF-β1 signaling as identified by Smad3 phosphorylation and activation of a partial plasminogen activator inhibitor-1 promoter (PAI-1, a transcriptional target of Smad3), but prevents non-canonical p38 MAPK phosphorylation. It was initially suspected that 5-HT(2B) antagonism prevents Src tyrosine kinase phosphorylation; however, we found that this is not the case and time-lapse microscopy indicates that 5-HT(2B) antagonism prevents non-canonical TGF-β1 signaling by physically arresting Src tyrosine kinase. This study demonstrates the necessity of non-canonical TGF-β1 signaling in leading to pathologic AVIC differentiation. Moreover, we believe that the results of this study suggest 5-HT(2B) antagonism as a novel therapeutic approach for CAVD that merits further investigation.
Copyright © 2012 Elsevier Ltd. All rights reserved.
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28 MeSH Terms
A stochastic multi-scale model of electrical function in normal and depleted ICC networks.
Gao J, Du P, Archer R, O'Grady G, Gibbons SJ, Farrugia G, Cheng LK, Pullan AJ
(2011) IEEE Trans Biomed Eng 58: 3451-5
MeSH Terms: Algorithms, Animals, Computer Simulation, Diagnostic Techniques, Digestive System, Electrodiagnosis, Interstitial Cells of Cajal, Mice, Mice, Knockout, Models, Biological, Receptor, Serotonin, 5-HT2B, Reproducibility of Results
Show Abstract · Added April 26, 2016
Multi-scale modeling has become a productive strategy for quantifying interstitial cells of Cajal (ICC) network structure-function relationships, but the lack of large-scale ICC network imaging data currently limits modeling progress. The single normal equation simulation (SNESIM) algorithm was utilized to generate realistic virtual images of small real wild-type (WT) and 5-HT(2B)-receptor knockout (Htr2b(-/-)) mice ICC networks. Two metrics were developed to validate the performance of the algorithm: 1) network density, which is the proportion of ICC in the tissue; and 2) connectivity, which reflects the degree of connectivity of the ICC network. Following validation, the SNESIM algorithm was modified to allow variation in the degree of ICC network depletion. ICC networks from a range of depletion severities were generated, and the electrical activity over these networks was simulated. The virtual ICC networks generated by the original SNESIM algorithm were similar to that of their real counterparts. The electrical activity simulations showed that the maximum current density magnitude increased as the network density increased. In conclusion, the SNESIM algorithm is an effective tool for generating realistic virtual ICC networks. The modified SNESIM algorithm can be used with simulation techniques to quantify the physiological consequences of ICC network depletion at various physical scales.
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11 MeSH Terms
Serotonin receptors and heart valve disease--it was meant 2B.
Hutcheson JD, Setola V, Roth BL, Merryman WD
(2011) Pharmacol Ther 132: 146-57
MeSH Terms: Animals, Carcinoid Heart Disease, Heart Valve Diseases, Humans, Receptor, Serotonin, 5-HT2B, Serotonin Agents
Show Abstract · Added February 12, 2015
Carcinoid heart disease was one of the first valvular pathologies studied in molecular detail, and early research identified serotonin produced by oncogenic enterochromaffin cells as the likely culprit in causing changes in heart valve tissue. Researchers and physicians in the mid-1960s noted a connection between the use of several ergot-derived medications with structures similar to serotonin and the development of heart valve pathologies similar to those observed in carcinoid patients. The exact serotonergic target that mediated valvular pathogenesis remained a mystery for many years until similar cases were reported in patients using the popular diet drug Fen-Phen in the late 1990s. The Fen-Phen episode sparked renewed interest in serotonin-mediated valve disease, and studies led to the identification of the 5-HT(2B) receptor as the likely molecular target leading to heart valve tissue fibrosis. Subsequent studies have identified numerous other activators of the 5-HT(2B) receptor, and consequently, the use of many of these molecules has been linked to heart valve disease. Herein, we: review the molecular properties of the 5-HT(2B) receptor including factors that differentiate the 5-HT(2B) receptor from other 5-HT receptor subtypes, discuss the studies that led to the identification of the 5-HT(2B) receptor as the mediator of heart valve disease, present current efforts to identify potential valvulopathogens by screening for 5-HT(2B) receptor activity, and speculate on potential therapeutic benefits of 5-HT(2B) receptor targeting.
Copyright © 2011. Published by Elsevier Inc.
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6 MeSH Terms
Tissue-specific mathematical models of slow wave entrainment in wild-type and 5-HT(2B) knockout mice with altered interstitial cells of Cajal networks.
Du P, O'Grady G, Gibbons SJ, Yassi R, Lees-Green R, Farrugia G, Cheng LK, Pullan AJ
(2010) Biophys J 98: 1772-81
MeSH Terms: Animals, Biophysical Phenomena, Gastrointestinal Tract, Interstitial Cells of Cajal, Intestine, Small, Kinetics, Mice, Mice, Knockout, Models, Biological, Myenteric Plexus, Organ Specificity, Receptor, Serotonin, 5-HT2B
Show Abstract · Added April 26, 2016
Gastrointestinal slow waves are generated within networks of interstitial cells of Cajal (ICCs). In the intact tissue, slow waves are entrained to neighboring ICCs with higher intrinsic frequencies, leading to active propagation of slow waves. Degradation of ICC networks in humans is associated with motility disorders; however, the pathophysiological mechanisms of this relationship are uncertain. A recently developed biophysically based mathematical model of ICC was adopted and updated to simulate entrainment of slow waves. Simulated slow wave propagation was successfully entrained in a one-dimensional model, which contained a gradient of intrinsic frequencies. Slow wave propagation was then simulated in tissue models which contained a realistic two-dimensional microstructure of the myenteric ICC networks translated from wild-type (WT) and 5-HT(2B) knockout (degraded) mouse jejunum. The results showed that the peak current density in the WT model was 0.49 muA mm(-2) higher than the 5-HT(2B) knockout model, and the intracellular Ca(2+) density after 400 ms was 0.26 mM mm(-2) higher in the WT model. In conclusion, tissue-specific models of slow waves are presented, and simulations quantitatively demonstrated physiological differences between WT and 5-HT(2B) knockout models. This study provides a framework for evaluating how ICC network degradation may impair slow wave propagation and ultimately motility and transit.
Copyright (c) 2010 Biophysical Society. Published by Elsevier Inc. All rights reserved.
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12 MeSH Terms