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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...

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Detalles Bibliográficos
Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2013
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
Descripción
Sumario: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.