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Substrate Stiffness Regulates Cholesterol Efflux in Smooth Muscle Cells

The infiltration and deposition of cholesterol in the arterial wall play an important role in the initiation and development of atherosclerosis. Smooth muscle cells (SMCs) are the major cell type in the intima. Upon exposure to cholesterol, SMCs may undergo a phenotype switching into foam cells. Mea...

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Autores principales: Mao, Xiuli, Tan, Yiling, Wang, Huali, Li, Song, Zhou, Yue
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8168435/
https://www.ncbi.nlm.nih.gov/pubmed/34084769
http://dx.doi.org/10.3389/fcell.2021.648715
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author Mao, Xiuli
Tan, Yiling
Wang, Huali
Li, Song
Zhou, Yue
author_facet Mao, Xiuli
Tan, Yiling
Wang, Huali
Li, Song
Zhou, Yue
author_sort Mao, Xiuli
collection PubMed
description The infiltration and deposition of cholesterol in the arterial wall play an important role in the initiation and development of atherosclerosis. Smooth muscle cells (SMCs) are the major cell type in the intima. Upon exposure to cholesterol, SMCs may undergo a phenotype switching into foam cells. Meanwhile, the pathological processes of the blood vessel such as cholesterol deposition and calcification induce the changes in the substrate stiffness around SMCs. However, whether substrate stiffness affects the cholesterol accumulation in SMCs and the formation of foam cells is not well-understood. In this study, SMCs were cultured on the substrates with different stiffnesses ranging from 1 to 100 kPa and treated with cholesterol. We found that cholesterol accumulation in SMCs was higher on 1 and 100 kPa substrates than that on intermediate stiffness at 40 kPa; consistently, total cholesterol (TC) content on 1 and 100 kPa substrates was also higher. As a result, the accumulation of cholesterol increased the expression of macrophage marker CD68 and downregulated SMC contractile marker smooth muscle α-actin (ACTA2). Furthermore, the mRNA and protein expression level of cholesterol efflux gene ATP-binding cassette transporter A1 (ABCA1) was much higher on 40 kPa substrate. With the treatment of a liver X receptor (LXR) agonist GW3965, the expression of ABCA1 increased and cholesterol loading decreased, showing an additive effect with substrate stiffness. In contrast, inhibition of LXR decreased ABCA1 gene expression and increased cholesterol accumulation in SMCs. Consistently, when ABCA1 gene was knockdown, the cholesterol accumulation was increased in SMCs on all substrates with different stiffness. These results revealed that substrate stiffness played an important role on SMCs cholesterol accumulation by regulating the ABCA1 expression. Our findings on the effects of substrate stiffness on cholesterol efflux unravel a new mechanism of biophysical regulation of cholesterol metabolism and SMC phenotype, and provide a rational basis for the development of novel therapies.
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spelling pubmed-81684352021-06-02 Substrate Stiffness Regulates Cholesterol Efflux in Smooth Muscle Cells Mao, Xiuli Tan, Yiling Wang, Huali Li, Song Zhou, Yue Front Cell Dev Biol Cell and Developmental Biology The infiltration and deposition of cholesterol in the arterial wall play an important role in the initiation and development of atherosclerosis. Smooth muscle cells (SMCs) are the major cell type in the intima. Upon exposure to cholesterol, SMCs may undergo a phenotype switching into foam cells. Meanwhile, the pathological processes of the blood vessel such as cholesterol deposition and calcification induce the changes in the substrate stiffness around SMCs. However, whether substrate stiffness affects the cholesterol accumulation in SMCs and the formation of foam cells is not well-understood. In this study, SMCs were cultured on the substrates with different stiffnesses ranging from 1 to 100 kPa and treated with cholesterol. We found that cholesterol accumulation in SMCs was higher on 1 and 100 kPa substrates than that on intermediate stiffness at 40 kPa; consistently, total cholesterol (TC) content on 1 and 100 kPa substrates was also higher. As a result, the accumulation of cholesterol increased the expression of macrophage marker CD68 and downregulated SMC contractile marker smooth muscle α-actin (ACTA2). Furthermore, the mRNA and protein expression level of cholesterol efflux gene ATP-binding cassette transporter A1 (ABCA1) was much higher on 40 kPa substrate. With the treatment of a liver X receptor (LXR) agonist GW3965, the expression of ABCA1 increased and cholesterol loading decreased, showing an additive effect with substrate stiffness. In contrast, inhibition of LXR decreased ABCA1 gene expression and increased cholesterol accumulation in SMCs. Consistently, when ABCA1 gene was knockdown, the cholesterol accumulation was increased in SMCs on all substrates with different stiffness. These results revealed that substrate stiffness played an important role on SMCs cholesterol accumulation by regulating the ABCA1 expression. Our findings on the effects of substrate stiffness on cholesterol efflux unravel a new mechanism of biophysical regulation of cholesterol metabolism and SMC phenotype, and provide a rational basis for the development of novel therapies. Frontiers Media S.A. 2021-05-18 /pmc/articles/PMC8168435/ /pubmed/34084769 http://dx.doi.org/10.3389/fcell.2021.648715 Text en Copyright © 2021 Mao, Tan, Wang, Li and Zhou. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Cell and Developmental Biology
Mao, Xiuli
Tan, Yiling
Wang, Huali
Li, Song
Zhou, Yue
Substrate Stiffness Regulates Cholesterol Efflux in Smooth Muscle Cells
title Substrate Stiffness Regulates Cholesterol Efflux in Smooth Muscle Cells
title_full Substrate Stiffness Regulates Cholesterol Efflux in Smooth Muscle Cells
title_fullStr Substrate Stiffness Regulates Cholesterol Efflux in Smooth Muscle Cells
title_full_unstemmed Substrate Stiffness Regulates Cholesterol Efflux in Smooth Muscle Cells
title_short Substrate Stiffness Regulates Cholesterol Efflux in Smooth Muscle Cells
title_sort substrate stiffness regulates cholesterol efflux in smooth muscle cells
topic Cell and Developmental Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8168435/
https://www.ncbi.nlm.nih.gov/pubmed/34084769
http://dx.doi.org/10.3389/fcell.2021.648715
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