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Smooth Muscle-Targeted Overexpression of Peroxisome Proliferator Activated Receptor-γ Disrupts Vascular Wall Structure and Function

Activation of the nuclear hormone receptor, PPARγ, with pharmacological agonists promotes a contractile vascular smooth muscle cell phenotype and reduces oxidative stress and cell proliferation, particularly under pathological conditions including vascular injury, restenosis, and atherosclerosis. Ho...

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Autores principales: Kleinhenz, Jennifer M., Murphy, Tamara C., Pokutta-Paskaleva, Anastassia P., Gleason, Rudolph L., Lyle, Alicia N., Taylor, W. Robert, Blount, Mitsi A., Cheng, Juan, Yang, Qinglin, Sutliff, Roy L., Hart, C. Michael
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4599849/
https://www.ncbi.nlm.nih.gov/pubmed/26451838
http://dx.doi.org/10.1371/journal.pone.0139756
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author Kleinhenz, Jennifer M.
Murphy, Tamara C.
Pokutta-Paskaleva, Anastassia P.
Gleason, Rudolph L.
Lyle, Alicia N.
Taylor, W. Robert
Blount, Mitsi A.
Cheng, Juan
Yang, Qinglin
Sutliff, Roy L.
Hart, C. Michael
author_facet Kleinhenz, Jennifer M.
Murphy, Tamara C.
Pokutta-Paskaleva, Anastassia P.
Gleason, Rudolph L.
Lyle, Alicia N.
Taylor, W. Robert
Blount, Mitsi A.
Cheng, Juan
Yang, Qinglin
Sutliff, Roy L.
Hart, C. Michael
author_sort Kleinhenz, Jennifer M.
collection PubMed
description Activation of the nuclear hormone receptor, PPARγ, with pharmacological agonists promotes a contractile vascular smooth muscle cell phenotype and reduces oxidative stress and cell proliferation, particularly under pathological conditions including vascular injury, restenosis, and atherosclerosis. However, pharmacological agonists activate both PPARγ-dependent and -independent mechanisms in multiple cell types confounding efforts to clarify the precise role of PPARγ in smooth muscle cell structure and function in vivo. We, therefore, designed and characterized a mouse model with smooth muscle cell-targeted PPARγ overexpression (smPPARγOE). Our results demonstrate that smPPARγOE attenuated contractile responses in aortic rings, increased aortic compliance, caused aortic dilatation, and reduced mean arterial pressure. Molecular characterization revealed that compared to littermate control mice, aortas from smPPARγOE mice expressed lower levels of contractile proteins and increased levels of adipocyte-specific transcripts. Morphological analysis demonstrated increased lipid deposition in the vascular media and in smooth muscle of extravascular tissues. In vitro adenoviral-mediated PPARγ overexpression in human aortic smooth muscle cells similarly increased adipocyte markers and lipid uptake. The findings demonstrate that smooth muscle PPARγ overexpression disrupts vascular wall structure and function, emphasizing that balanced PPARγ activity is essential for vascular smooth muscle homeostasis.
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spelling pubmed-45998492015-10-20 Smooth Muscle-Targeted Overexpression of Peroxisome Proliferator Activated Receptor-γ Disrupts Vascular Wall Structure and Function Kleinhenz, Jennifer M. Murphy, Tamara C. Pokutta-Paskaleva, Anastassia P. Gleason, Rudolph L. Lyle, Alicia N. Taylor, W. Robert Blount, Mitsi A. Cheng, Juan Yang, Qinglin Sutliff, Roy L. Hart, C. Michael PLoS One Research Article Activation of the nuclear hormone receptor, PPARγ, with pharmacological agonists promotes a contractile vascular smooth muscle cell phenotype and reduces oxidative stress and cell proliferation, particularly under pathological conditions including vascular injury, restenosis, and atherosclerosis. However, pharmacological agonists activate both PPARγ-dependent and -independent mechanisms in multiple cell types confounding efforts to clarify the precise role of PPARγ in smooth muscle cell structure and function in vivo. We, therefore, designed and characterized a mouse model with smooth muscle cell-targeted PPARγ overexpression (smPPARγOE). Our results demonstrate that smPPARγOE attenuated contractile responses in aortic rings, increased aortic compliance, caused aortic dilatation, and reduced mean arterial pressure. Molecular characterization revealed that compared to littermate control mice, aortas from smPPARγOE mice expressed lower levels of contractile proteins and increased levels of adipocyte-specific transcripts. Morphological analysis demonstrated increased lipid deposition in the vascular media and in smooth muscle of extravascular tissues. In vitro adenoviral-mediated PPARγ overexpression in human aortic smooth muscle cells similarly increased adipocyte markers and lipid uptake. The findings demonstrate that smooth muscle PPARγ overexpression disrupts vascular wall structure and function, emphasizing that balanced PPARγ activity is essential for vascular smooth muscle homeostasis. Public Library of Science 2015-10-09 /pmc/articles/PMC4599849/ /pubmed/26451838 http://dx.doi.org/10.1371/journal.pone.0139756 Text en https://creativecommons.org/publicdomain/zero/1.0/ This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration, which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose.
spellingShingle Research Article
Kleinhenz, Jennifer M.
Murphy, Tamara C.
Pokutta-Paskaleva, Anastassia P.
Gleason, Rudolph L.
Lyle, Alicia N.
Taylor, W. Robert
Blount, Mitsi A.
Cheng, Juan
Yang, Qinglin
Sutliff, Roy L.
Hart, C. Michael
Smooth Muscle-Targeted Overexpression of Peroxisome Proliferator Activated Receptor-γ Disrupts Vascular Wall Structure and Function
title Smooth Muscle-Targeted Overexpression of Peroxisome Proliferator Activated Receptor-γ Disrupts Vascular Wall Structure and Function
title_full Smooth Muscle-Targeted Overexpression of Peroxisome Proliferator Activated Receptor-γ Disrupts Vascular Wall Structure and Function
title_fullStr Smooth Muscle-Targeted Overexpression of Peroxisome Proliferator Activated Receptor-γ Disrupts Vascular Wall Structure and Function
title_full_unstemmed Smooth Muscle-Targeted Overexpression of Peroxisome Proliferator Activated Receptor-γ Disrupts Vascular Wall Structure and Function
title_short Smooth Muscle-Targeted Overexpression of Peroxisome Proliferator Activated Receptor-γ Disrupts Vascular Wall Structure and Function
title_sort smooth muscle-targeted overexpression of peroxisome proliferator activated receptor-γ disrupts vascular wall structure and function
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4599849/
https://www.ncbi.nlm.nih.gov/pubmed/26451838
http://dx.doi.org/10.1371/journal.pone.0139756
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