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TGF-β inhibits the uptake of modified low density lipoprotein by human macrophages through a Smad-dependent pathway: A dominant role for Smad-2
The anti-atherogenic cytokine, TGF-β, plays a key role during macrophage foam cell formation by modulating the expression of key genes involved in the control of cholesterol homeostasis. Unfortunately, the molecular mechanisms underlying these actions of TGF-β remain poorly understood. In this study...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier Pub. Co
2012
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3497875/ https://www.ncbi.nlm.nih.gov/pubmed/22705205 http://dx.doi.org/10.1016/j.bbadis.2012.06.002 |
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author | Michael, Daryn R. Salter, Rebecca C. Ramji, Dipak P. |
author_facet | Michael, Daryn R. Salter, Rebecca C. Ramji, Dipak P. |
author_sort | Michael, Daryn R. |
collection | PubMed |
description | The anti-atherogenic cytokine, TGF-β, plays a key role during macrophage foam cell formation by modulating the expression of key genes involved in the control of cholesterol homeostasis. Unfortunately, the molecular mechanisms underlying these actions of TGF-β remain poorly understood. In this study we examine the effect of TGF-β on macrophage cholesterol homeostasis and delineate the role of Smads-2 and ‐3 during this process. Western blot analysis showed that TGF-β induces a rapid phosphorylation-dependent activation of Smad-2 and ‐3 in THP-1 and primary human monocyte-derived macrophages. Small interfering RNA-mediated knockdown of Smad-2/3 expression showed that the TGF-β-mediated regulation of key genes implicated in the uptake of modified low density lipoproteins and the efflux of cholesterol from foam cells was Smad-dependent. Additionally, through the use of virally delivered Smad-2 and/or Smad-3 short hairpin RNA, we demonstrate that TGF-β inhibits the uptake of modified LDL by macrophages through a Smad-dependent mechanism and that the TGF-β-mediated regulation of CD36, lipoprotein lipase and scavenger receptor-A gene expression was dependent on Smad-2. These studies reveal a crucial role for Smad signaling, particularly Smad-2, in the inhibition of foam cell formation by TGF-β through the regulation of expression of key genes involved in the control of macrophage cholesterol homeostasis. |
format | Online Article Text |
id | pubmed-3497875 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | Elsevier Pub. Co |
record_format | MEDLINE/PubMed |
spelling | pubmed-34978752012-11-14 TGF-β inhibits the uptake of modified low density lipoprotein by human macrophages through a Smad-dependent pathway: A dominant role for Smad-2 Michael, Daryn R. Salter, Rebecca C. Ramji, Dipak P. Biochim Biophys Acta Article The anti-atherogenic cytokine, TGF-β, plays a key role during macrophage foam cell formation by modulating the expression of key genes involved in the control of cholesterol homeostasis. Unfortunately, the molecular mechanisms underlying these actions of TGF-β remain poorly understood. In this study we examine the effect of TGF-β on macrophage cholesterol homeostasis and delineate the role of Smads-2 and ‐3 during this process. Western blot analysis showed that TGF-β induces a rapid phosphorylation-dependent activation of Smad-2 and ‐3 in THP-1 and primary human monocyte-derived macrophages. Small interfering RNA-mediated knockdown of Smad-2/3 expression showed that the TGF-β-mediated regulation of key genes implicated in the uptake of modified low density lipoproteins and the efflux of cholesterol from foam cells was Smad-dependent. Additionally, through the use of virally delivered Smad-2 and/or Smad-3 short hairpin RNA, we demonstrate that TGF-β inhibits the uptake of modified LDL by macrophages through a Smad-dependent mechanism and that the TGF-β-mediated regulation of CD36, lipoprotein lipase and scavenger receptor-A gene expression was dependent on Smad-2. These studies reveal a crucial role for Smad signaling, particularly Smad-2, in the inhibition of foam cell formation by TGF-β through the regulation of expression of key genes involved in the control of macrophage cholesterol homeostasis. Elsevier Pub. Co 2012-10 /pmc/articles/PMC3497875/ /pubmed/22705205 http://dx.doi.org/10.1016/j.bbadis.2012.06.002 Text en © 2012 Elsevier B.V. https://creativecommons.org/licenses/by-nc-nd/3.0/ Open Access under CC BY-NC-ND 3.0 (https://creativecommons.org/licenses/by-nc-nd/3.0/) license |
spellingShingle | Article Michael, Daryn R. Salter, Rebecca C. Ramji, Dipak P. TGF-β inhibits the uptake of modified low density lipoprotein by human macrophages through a Smad-dependent pathway: A dominant role for Smad-2 |
title | TGF-β inhibits the uptake of modified low density lipoprotein by human macrophages through a Smad-dependent pathway: A dominant role for Smad-2 |
title_full | TGF-β inhibits the uptake of modified low density lipoprotein by human macrophages through a Smad-dependent pathway: A dominant role for Smad-2 |
title_fullStr | TGF-β inhibits the uptake of modified low density lipoprotein by human macrophages through a Smad-dependent pathway: A dominant role for Smad-2 |
title_full_unstemmed | TGF-β inhibits the uptake of modified low density lipoprotein by human macrophages through a Smad-dependent pathway: A dominant role for Smad-2 |
title_short | TGF-β inhibits the uptake of modified low density lipoprotein by human macrophages through a Smad-dependent pathway: A dominant role for Smad-2 |
title_sort | tgf-β inhibits the uptake of modified low density lipoprotein by human macrophages through a smad-dependent pathway: a dominant role for smad-2 |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3497875/ https://www.ncbi.nlm.nih.gov/pubmed/22705205 http://dx.doi.org/10.1016/j.bbadis.2012.06.002 |
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