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Ablation of Galectin-12 Inhibits Atherosclerosis through Enhancement of M2 Macrophage Polarization

The formation of foam cells, which are macrophages that have engulfed oxidized low-density lipoprotein (OxLDL), constitutes the first stage in the development of atherosclerosis. Previously, we found that knocking down galectin-12, a negative regulator of lipolysis, leads to reduced secretion of mon...

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Autores principales: Lin, En-Shyh, Hsu, Yu-An, Chang, Ching-Yao, Lin, Hui-Ju, Chen, Chih Sheng, Wan, Lei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7432701/
https://www.ncbi.nlm.nih.gov/pubmed/32752134
http://dx.doi.org/10.3390/ijms21155511
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author Lin, En-Shyh
Hsu, Yu-An
Chang, Ching-Yao
Lin, Hui-Ju
Chen, Chih Sheng
Wan, Lei
author_facet Lin, En-Shyh
Hsu, Yu-An
Chang, Ching-Yao
Lin, Hui-Ju
Chen, Chih Sheng
Wan, Lei
author_sort Lin, En-Shyh
collection PubMed
description The formation of foam cells, which are macrophages that have engulfed oxidized low-density lipoprotein (OxLDL), constitutes the first stage in the development of atherosclerosis. Previously, we found that knocking down galectin-12, a negative regulator of lipolysis, leads to reduced secretion of monocyte chemoattractant protein-1 (MCP-1), a chemokine that plays an important role in atherosclerosis. This prompted us to study the role of galectin-12 in atherosclerosis. With that aim, we examined foam cell formation in Gal12(‒/‒) murine macrophages exposed to OxLDL and acetylated LDL (AcLDL). Then, we generated an LDL receptor and galectin-12 double knockout (DKO) mice and studied the effect of galectin-12 on macrophage function and atherosclerosis. Lastly, we evaluated the role of galectin-12 in human THP-1 macrophages using a doxycycline-inducible conditional knockdown system. Galectin-12 knockout significantly inhibited foam cell formation in murine macrophages through the downregulation of cluster of differentiation 36 (CD36), and the upregulation of ATP Binding Cassette Subfamily A Member 1 (ABCA1), ATP Binding Cassette Subfamily G Member 1 (ABCG1), and scavenger receptor class B type 1 (SRB1). Consistent with this, galectin-12 knockdown inhibited foam cell formation in human macrophages. In addition, the ablation of galectin-12 promoted M2 macrophage polarization in human and murine macrophages as evidenced by the upregulation of the M2 marker genes, CD206 and CD163, and downregulation of the M1 cytokines, tumor necrosis factor α (TNF- α), interleukin-6 (IL-6), and MCP-1. Moreover, the ablation of galectin-12 decreased atherosclerosis formation in DKO mice. Based on these results, we propose galectin-12 as a potential therapeutic target for atherosclerosis.
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spelling pubmed-74327012020-08-27 Ablation of Galectin-12 Inhibits Atherosclerosis through Enhancement of M2 Macrophage Polarization Lin, En-Shyh Hsu, Yu-An Chang, Ching-Yao Lin, Hui-Ju Chen, Chih Sheng Wan, Lei Int J Mol Sci Article The formation of foam cells, which are macrophages that have engulfed oxidized low-density lipoprotein (OxLDL), constitutes the first stage in the development of atherosclerosis. Previously, we found that knocking down galectin-12, a negative regulator of lipolysis, leads to reduced secretion of monocyte chemoattractant protein-1 (MCP-1), a chemokine that plays an important role in atherosclerosis. This prompted us to study the role of galectin-12 in atherosclerosis. With that aim, we examined foam cell formation in Gal12(‒/‒) murine macrophages exposed to OxLDL and acetylated LDL (AcLDL). Then, we generated an LDL receptor and galectin-12 double knockout (DKO) mice and studied the effect of galectin-12 on macrophage function and atherosclerosis. Lastly, we evaluated the role of galectin-12 in human THP-1 macrophages using a doxycycline-inducible conditional knockdown system. Galectin-12 knockout significantly inhibited foam cell formation in murine macrophages through the downregulation of cluster of differentiation 36 (CD36), and the upregulation of ATP Binding Cassette Subfamily A Member 1 (ABCA1), ATP Binding Cassette Subfamily G Member 1 (ABCG1), and scavenger receptor class B type 1 (SRB1). Consistent with this, galectin-12 knockdown inhibited foam cell formation in human macrophages. In addition, the ablation of galectin-12 promoted M2 macrophage polarization in human and murine macrophages as evidenced by the upregulation of the M2 marker genes, CD206 and CD163, and downregulation of the M1 cytokines, tumor necrosis factor α (TNF- α), interleukin-6 (IL-6), and MCP-1. Moreover, the ablation of galectin-12 decreased atherosclerosis formation in DKO mice. Based on these results, we propose galectin-12 as a potential therapeutic target for atherosclerosis. MDPI 2020-07-31 /pmc/articles/PMC7432701/ /pubmed/32752134 http://dx.doi.org/10.3390/ijms21155511 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Lin, En-Shyh
Hsu, Yu-An
Chang, Ching-Yao
Lin, Hui-Ju
Chen, Chih Sheng
Wan, Lei
Ablation of Galectin-12 Inhibits Atherosclerosis through Enhancement of M2 Macrophage Polarization
title Ablation of Galectin-12 Inhibits Atherosclerosis through Enhancement of M2 Macrophage Polarization
title_full Ablation of Galectin-12 Inhibits Atherosclerosis through Enhancement of M2 Macrophage Polarization
title_fullStr Ablation of Galectin-12 Inhibits Atherosclerosis through Enhancement of M2 Macrophage Polarization
title_full_unstemmed Ablation of Galectin-12 Inhibits Atherosclerosis through Enhancement of M2 Macrophage Polarization
title_short Ablation of Galectin-12 Inhibits Atherosclerosis through Enhancement of M2 Macrophage Polarization
title_sort ablation of galectin-12 inhibits atherosclerosis through enhancement of m2 macrophage polarization
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7432701/
https://www.ncbi.nlm.nih.gov/pubmed/32752134
http://dx.doi.org/10.3390/ijms21155511
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