Essential role of TGF-beta/Smad pathway on statin dependent vascular smooth muscle cell regulation.

<h4>Background</h4>The 3-hydroxy-3-methylglutaryl CoA reductase inhibitors (also called statins) exert proven beneficial effects on cardiovascular diseases. Recent data suggest a protective role for Transforming Growth Factor-beta (TGF-beta) in atherosclerosis by regulating the balance b...

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Autores principales:	Juan Rodríguez-Vita, Eva Sánchez-Galán, Beatriz Santamaría, Elsa Sánchez-López, Raquel Rodrigues-Díez, Luís Miguel Blanco-Colio, Jesús Egido, Alberto Ortiz, Marta Ruiz-Ortega
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2008
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/19fe1cd43ec740cfa3a7dfd9cc6d979d
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spelling	oai:doaj.org-article:19fe1cd43ec740cfa3a7dfd9cc6d979d2021-11-25T06:18:10ZEssential role of TGF-beta/Smad pathway on statin dependent vascular smooth muscle cell regulation.1932-620310.1371/journal.pone.0003959https://doaj.org/article/19fe1cd43ec740cfa3a7dfd9cc6d979d2008-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/19088845/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4>The 3-hydroxy-3-methylglutaryl CoA reductase inhibitors (also called statins) exert proven beneficial effects on cardiovascular diseases. Recent data suggest a protective role for Transforming Growth Factor-beta (TGF-beta) in atherosclerosis by regulating the balance between inflammation and extracellular matrix accumulation. However, there are no studies about the effect of statins on TGF-beta/Smad pathway in atherosclerosis and vascular cells.<h4>Methodology</h4>In cultured vascular smooth muscle cells (VSMCs) statins enhanced Smad pathway activation caused by TGF-beta. In addition, statins upregulated TGF-beta receptor type II (TRII), and increased TGF-beta synthesis and TGF-beta/Smad-dependent actions. In this sense, statins, through Smad activation, render VSMCs more susceptible to TGF-beta induced apoptosis and increased TGF-beta-mediated ECM production. It is well documented that high doses of statins induce apoptosis in cultured VSMC in the presence of serum; however the precise mechanism of this effect remains to be elucidated. We have found that statins-induced apoptosis was mediated by TGF-beta/Smad pathway. Finally, we have described that RhoA inhibition is a common intracellular mechanisms involved in statins effects. The in vivo relevance of these findings was assessed in an experimental model of atherosclerosis in apolipoprotein E deficient mice: Treatment with Atorvastatin increased Smad3 phosphorylation and TRII overexpression, associated to elevated ECM deposition in the VSMCs within atheroma plaques, while apoptosis was not detected.<h4>Conclusions</h4>Statins enhance TGF-beta/Smad pathway, regulating ligand levels, receptor, main signaling pathway and cellular responses of VSMC, including apoptosis and ECM accumulation. Our findings show that TGF-beta/Smad pathway is essential for statins-dependent actions in VSMCs.Juan Rodríguez-VitaEva Sánchez-GalánBeatriz SantamaríaElsa Sánchez-LópezRaquel Rodrigues-DíezLuís Miguel Blanco-ColioJesús EgidoAlberto OrtizMarta Ruiz-OrtegaMarta Ruiz-OrtegaPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 3, Iss 12, p e3959 (2008)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Juan Rodríguez-Vita Eva Sánchez-Galán Beatriz Santamaría Elsa Sánchez-López Raquel Rodrigues-Díez Luís Miguel Blanco-Colio Jesús Egido Alberto Ortiz Marta Ruiz-Ortega Marta Ruiz-Ortega Essential role of TGF-beta/Smad pathway on statin dependent vascular smooth muscle cell regulation.
description	<h4>Background</h4>The 3-hydroxy-3-methylglutaryl CoA reductase inhibitors (also called statins) exert proven beneficial effects on cardiovascular diseases. Recent data suggest a protective role for Transforming Growth Factor-beta (TGF-beta) in atherosclerosis by regulating the balance between inflammation and extracellular matrix accumulation. However, there are no studies about the effect of statins on TGF-beta/Smad pathway in atherosclerosis and vascular cells.<h4>Methodology</h4>In cultured vascular smooth muscle cells (VSMCs) statins enhanced Smad pathway activation caused by TGF-beta. In addition, statins upregulated TGF-beta receptor type II (TRII), and increased TGF-beta synthesis and TGF-beta/Smad-dependent actions. In this sense, statins, through Smad activation, render VSMCs more susceptible to TGF-beta induced apoptosis and increased TGF-beta-mediated ECM production. It is well documented that high doses of statins induce apoptosis in cultured VSMC in the presence of serum; however the precise mechanism of this effect remains to be elucidated. We have found that statins-induced apoptosis was mediated by TGF-beta/Smad pathway. Finally, we have described that RhoA inhibition is a common intracellular mechanisms involved in statins effects. The in vivo relevance of these findings was assessed in an experimental model of atherosclerosis in apolipoprotein E deficient mice: Treatment with Atorvastatin increased Smad3 phosphorylation and TRII overexpression, associated to elevated ECM deposition in the VSMCs within atheroma plaques, while apoptosis was not detected.<h4>Conclusions</h4>Statins enhance TGF-beta/Smad pathway, regulating ligand levels, receptor, main signaling pathway and cellular responses of VSMC, including apoptosis and ECM accumulation. Our findings show that TGF-beta/Smad pathway is essential for statins-dependent actions in VSMCs.
format	article
author	Juan Rodríguez-Vita Eva Sánchez-Galán Beatriz Santamaría Elsa Sánchez-López Raquel Rodrigues-Díez Luís Miguel Blanco-Colio Jesús Egido Alberto Ortiz Marta Ruiz-Ortega Marta Ruiz-Ortega
author_facet	Juan Rodríguez-Vita Eva Sánchez-Galán Beatriz Santamaría Elsa Sánchez-López Raquel Rodrigues-Díez Luís Miguel Blanco-Colio Jesús Egido Alberto Ortiz Marta Ruiz-Ortega Marta Ruiz-Ortega
author_sort	Juan Rodríguez-Vita
title	Essential role of TGF-beta/Smad pathway on statin dependent vascular smooth muscle cell regulation.
title_short	Essential role of TGF-beta/Smad pathway on statin dependent vascular smooth muscle cell regulation.
title_full	Essential role of TGF-beta/Smad pathway on statin dependent vascular smooth muscle cell regulation.
title_fullStr	Essential role of TGF-beta/Smad pathway on statin dependent vascular smooth muscle cell regulation.
title_full_unstemmed	Essential role of TGF-beta/Smad pathway on statin dependent vascular smooth muscle cell regulation.
title_sort	essential role of tgf-beta/smad pathway on statin dependent vascular smooth muscle cell regulation.
publisher	Public Library of Science (PLoS)
publishDate	2008
url	https://doaj.org/article/19fe1cd43ec740cfa3a7dfd9cc6d979d
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Essential role of TGF-beta/Smad pathway on statin dependent vascular smooth muscle cell regulation.

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