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The smooth muscle-selective RhoGAP GRAF3 is a critical regulator of vascular tone and hypertension
Although hypertension is a worldwide health issue, an incomplete understanding of its etiology has hindered our ability to treat this complex disease. Here we identify arhgap42 (also known as GRAF3) as a Rho-specific GAP expressed specifically in smooth muscle cells in mice and humans. We show that...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2013
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4237314/ https://www.ncbi.nlm.nih.gov/pubmed/24335996 http://dx.doi.org/10.1038/ncomms3910 |
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author | Bai, Xue Lenhart, Kaitlin C. Bird, Kim E. Suen, Alisa A. Rojas, Mauricio Kakoki, Masao Li, Feng Smithies, Oliver Mack, Christopher P. Taylor, Joan M. |
author_facet | Bai, Xue Lenhart, Kaitlin C. Bird, Kim E. Suen, Alisa A. Rojas, Mauricio Kakoki, Masao Li, Feng Smithies, Oliver Mack, Christopher P. Taylor, Joan M. |
author_sort | Bai, Xue |
collection | PubMed |
description | Although hypertension is a worldwide health issue, an incomplete understanding of its etiology has hindered our ability to treat this complex disease. Here we identify arhgap42 (also known as GRAF3) as a Rho-specific GAP expressed specifically in smooth muscle cells in mice and humans. We show that GRAF3-deficient mice exhibit significant hypertension and increased pressor responses to angiotensin II and endothelin-1; these effects are prevented by treatment with the Rho-kinase inhibitor, Y-27632. RhoA activity and myosin light chain phosphorylation are elevated in GRAF3-depleted smooth muscle cells in vitro and in vivo, and isolated vessel segments from GRAF3-deficient mice show increased contractility. Taken together our data indicate that GRAF3-mediated inhibition of RhoA activity in vascular smooth muscle cells is necessary for maintaining normal blood pressure homeostasis. Moreover, these findings provide a potential mechanism for a hypertensive locus recently identified within arhgap42 and provide a foundation for the future development of innovative hypertension therapies. |
format | Online Article Text |
id | pubmed-4237314 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
record_format | MEDLINE/PubMed |
spelling | pubmed-42373142014-11-19 The smooth muscle-selective RhoGAP GRAF3 is a critical regulator of vascular tone and hypertension Bai, Xue Lenhart, Kaitlin C. Bird, Kim E. Suen, Alisa A. Rojas, Mauricio Kakoki, Masao Li, Feng Smithies, Oliver Mack, Christopher P. Taylor, Joan M. Nat Commun Article Although hypertension is a worldwide health issue, an incomplete understanding of its etiology has hindered our ability to treat this complex disease. Here we identify arhgap42 (also known as GRAF3) as a Rho-specific GAP expressed specifically in smooth muscle cells in mice and humans. We show that GRAF3-deficient mice exhibit significant hypertension and increased pressor responses to angiotensin II and endothelin-1; these effects are prevented by treatment with the Rho-kinase inhibitor, Y-27632. RhoA activity and myosin light chain phosphorylation are elevated in GRAF3-depleted smooth muscle cells in vitro and in vivo, and isolated vessel segments from GRAF3-deficient mice show increased contractility. Taken together our data indicate that GRAF3-mediated inhibition of RhoA activity in vascular smooth muscle cells is necessary for maintaining normal blood pressure homeostasis. Moreover, these findings provide a potential mechanism for a hypertensive locus recently identified within arhgap42 and provide a foundation for the future development of innovative hypertension therapies. 2013 /pmc/articles/PMC4237314/ /pubmed/24335996 http://dx.doi.org/10.1038/ncomms3910 Text en Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms |
spellingShingle | Article Bai, Xue Lenhart, Kaitlin C. Bird, Kim E. Suen, Alisa A. Rojas, Mauricio Kakoki, Masao Li, Feng Smithies, Oliver Mack, Christopher P. Taylor, Joan M. The smooth muscle-selective RhoGAP GRAF3 is a critical regulator of vascular tone and hypertension |
title | The smooth muscle-selective RhoGAP GRAF3 is a critical regulator of vascular tone and hypertension |
title_full | The smooth muscle-selective RhoGAP GRAF3 is a critical regulator of vascular tone and hypertension |
title_fullStr | The smooth muscle-selective RhoGAP GRAF3 is a critical regulator of vascular tone and hypertension |
title_full_unstemmed | The smooth muscle-selective RhoGAP GRAF3 is a critical regulator of vascular tone and hypertension |
title_short | The smooth muscle-selective RhoGAP GRAF3 is a critical regulator of vascular tone and hypertension |
title_sort | smooth muscle-selective rhogap graf3 is a critical regulator of vascular tone and hypertension |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4237314/ https://www.ncbi.nlm.nih.gov/pubmed/24335996 http://dx.doi.org/10.1038/ncomms3910 |
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