Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Michael, Daryn R., Salter, Rebecca C., Ramji, Dipak P.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier Pub. Co 2012
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
_version_ 1782249769451651072
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
work_keys_str_mv AT michaeldarynr tgfbinhibitstheuptakeofmodifiedlowdensitylipoproteinbyhumanmacrophagesthroughasmaddependentpathwayadominantroleforsmad2
AT salterrebeccac tgfbinhibitstheuptakeofmodifiedlowdensitylipoproteinbyhumanmacrophagesthroughasmaddependentpathwayadominantroleforsmad2
AT ramjidipakp tgfbinhibitstheuptakeofmodifiedlowdensitylipoproteinbyhumanmacrophagesthroughasmaddependentpathwayadominantroleforsmad2