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Serotonin 2B Receptor Antagonism Prevents Heritable Pulmonary Arterial Hypertension

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 recep...

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Autores principales: West, James D., Carrier, Erica J., Bloodworth, Nathaniel C., Schroer, Alison K., Chen, Peter, Ryzhova, Larisa M., Gladson, Santhi, Shay, Sheila, Hutcheson, Joshua D., Merryman, W. David
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4749293/
https://www.ncbi.nlm.nih.gov/pubmed/26863209
http://dx.doi.org/10.1371/journal.pone.0148657
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author West, James D.
Carrier, Erica J.
Bloodworth, Nathaniel C.
Schroer, Alison K.
Chen, Peter
Ryzhova, Larisa M.
Gladson, Santhi
Shay, Sheila
Hutcheson, Joshua D.
Merryman, W. David
author_facet West, James D.
Carrier, Erica J.
Bloodworth, Nathaniel C.
Schroer, Alison K.
Chen, Peter
Ryzhova, Larisa M.
Gladson, Santhi
Shay, Sheila
Hutcheson, Joshua D.
Merryman, W. David
author_sort West, James D.
collection PubMed
description 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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spelling pubmed-47492932016-02-26 Serotonin 2B Receptor Antagonism Prevents Heritable Pulmonary Arterial Hypertension West, James D. Carrier, Erica J. Bloodworth, Nathaniel C. Schroer, Alison K. Chen, Peter Ryzhova, Larisa M. Gladson, Santhi Shay, Sheila Hutcheson, Joshua D. Merryman, W. David PLoS One Research Article 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. Public Library of Science 2016-02-10 /pmc/articles/PMC4749293/ /pubmed/26863209 http://dx.doi.org/10.1371/journal.pone.0148657 Text en © 2016 West et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
West, James D.
Carrier, Erica J.
Bloodworth, Nathaniel C.
Schroer, Alison K.
Chen, Peter
Ryzhova, Larisa M.
Gladson, Santhi
Shay, Sheila
Hutcheson, Joshua D.
Merryman, W. David
Serotonin 2B Receptor Antagonism Prevents Heritable Pulmonary Arterial Hypertension
title Serotonin 2B Receptor Antagonism Prevents Heritable Pulmonary Arterial Hypertension
title_full Serotonin 2B Receptor Antagonism Prevents Heritable Pulmonary Arterial Hypertension
title_fullStr Serotonin 2B Receptor Antagonism Prevents Heritable Pulmonary Arterial Hypertension
title_full_unstemmed Serotonin 2B Receptor Antagonism Prevents Heritable Pulmonary Arterial Hypertension
title_short Serotonin 2B Receptor Antagonism Prevents Heritable Pulmonary Arterial Hypertension
title_sort serotonin 2b receptor antagonism prevents heritable pulmonary arterial hypertension
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4749293/
https://www.ncbi.nlm.nih.gov/pubmed/26863209
http://dx.doi.org/10.1371/journal.pone.0148657
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