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Diterpenoids inhibit ox-LDL-induced foam cell formation in RAW264.7 cells by promoting ABCA1 mediated cholesterol efflux

Introduction: Atherosclerosis is the main cause of many cardiovascular diseases and contributes to morbidity and mortality worldwide. The formation of macrophage-derived foam cells plays a critical role in the early stage of atherosclerosis pathogenesis. Diterpenoids found in the flowers of Callicar...

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Autores principales: Zhang, Cheng, Wu, Xuewen, Shi, Pengmin, Ma, Hongyu, Fang, Fei, Feng, Qianlang, Zhao, Shuang, Zhang, Ruipu, Huang, Jinyuan, Xu, Xinting, Xiao, Weilie, Cao, Guang, Ji, Xu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9877220/
https://www.ncbi.nlm.nih.gov/pubmed/36713845
http://dx.doi.org/10.3389/fphar.2023.1066758
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author Zhang, Cheng
Wu, Xuewen
Shi, Pengmin
Ma, Hongyu
Fang, Fei
Feng, Qianlang
Zhao, Shuang
Zhang, Ruipu
Huang, Jinyuan
Xu, Xinting
Xiao, Weilie
Cao, Guang
Ji, Xu
author_facet Zhang, Cheng
Wu, Xuewen
Shi, Pengmin
Ma, Hongyu
Fang, Fei
Feng, Qianlang
Zhao, Shuang
Zhang, Ruipu
Huang, Jinyuan
Xu, Xinting
Xiao, Weilie
Cao, Guang
Ji, Xu
author_sort Zhang, Cheng
collection PubMed
description Introduction: Atherosclerosis is the main cause of many cardiovascular diseases and contributes to morbidity and mortality worldwide. The formation of macrophage-derived foam cells plays a critical role in the early stage of atherosclerosis pathogenesis. Diterpenoids found in the flowers of Callicarpa rubella Lindl., a traditional Chinese medicine, have been reported to have anti-inflammatory activity. However, little is known about the effects of these diterpenoids on macrophage foam cell formation. Methods: A macrophage-derived foam cell formation model was established by treating RAW264.7 cells with oxidized low-density lipoprotein (ox-LDL) for 24 h. Oil red O staining were used to detect the intracellular lipids. The cholesterol efflux capacity was assayed by labeling cells with 22-NBD-cholesterol. Western blots and real-time PCRs were performed to quantify protein and mRNA expressions. Results: Two diterpenoid molecules, 14α-hydroxyisopimaric acid (C069002) and isopimaric acid (C069004), extracted from the flowers of Callicarpa rubella Lindl., significantly attenuated ox-LDL-induced foam cell formation in RAW264.7 macrophages. Further investigation showed that these two diterpenoids could promote cholesterol efflux from RAW264.7 macrophages to apolipoprotein A-I or high-density lipoproteins, which was associated with upregulated expression of ATP-binding cassette A1/G1 (ABCA1/G1), liver X receptor-α (LXRα), and peroxisome proliferator-activated receptor-γ (PPARγ). Unexpectedly, the diterpenoids C069002 and C069004 failed to enhance the mRNA transcription of the ABCG1 gene in macrophage-derived foam cells induced by ox-LDL. To evaluate the effects of diterpenoids on macrophage foam cell formation and determine the underlying mechanism, two drugs (lovastatin and rosiglitazone) were used as positive controls. Although both drugs could reduce macrophage foam cell formation and promote cholesterol efflux, they each had distinctive abilities to modulate the expression of cholesterol efflux-related genes. In contrast to lovastatin, rosiglitazone showed a similar influence on the expression of cholesterol efflux-related genes (including ABCA1, LXRα, and PPARγ) as the diterpenoids regardless of the presence or absence of ox-LDL, implying a similar mechanism by which they may exert atheroprotective effects. Conclusion: Our research indicates that diterpenoids effectively inhibit ox-LDL-induced macrophage foam cell formation by promoting cholesterol efflux from macrophages via the PPARγ-LXRα-ABCA1 pathway. Further investigation of diterpenoids as potential drugs for the treatment of atherosclerosis is warranted.
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spelling pubmed-98772202023-01-27 Diterpenoids inhibit ox-LDL-induced foam cell formation in RAW264.7 cells by promoting ABCA1 mediated cholesterol efflux Zhang, Cheng Wu, Xuewen Shi, Pengmin Ma, Hongyu Fang, Fei Feng, Qianlang Zhao, Shuang Zhang, Ruipu Huang, Jinyuan Xu, Xinting Xiao, Weilie Cao, Guang Ji, Xu Front Pharmacol Pharmacology Introduction: Atherosclerosis is the main cause of many cardiovascular diseases and contributes to morbidity and mortality worldwide. The formation of macrophage-derived foam cells plays a critical role in the early stage of atherosclerosis pathogenesis. Diterpenoids found in the flowers of Callicarpa rubella Lindl., a traditional Chinese medicine, have been reported to have anti-inflammatory activity. However, little is known about the effects of these diterpenoids on macrophage foam cell formation. Methods: A macrophage-derived foam cell formation model was established by treating RAW264.7 cells with oxidized low-density lipoprotein (ox-LDL) for 24 h. Oil red O staining were used to detect the intracellular lipids. The cholesterol efflux capacity was assayed by labeling cells with 22-NBD-cholesterol. Western blots and real-time PCRs were performed to quantify protein and mRNA expressions. Results: Two diterpenoid molecules, 14α-hydroxyisopimaric acid (C069002) and isopimaric acid (C069004), extracted from the flowers of Callicarpa rubella Lindl., significantly attenuated ox-LDL-induced foam cell formation in RAW264.7 macrophages. Further investigation showed that these two diterpenoids could promote cholesterol efflux from RAW264.7 macrophages to apolipoprotein A-I or high-density lipoproteins, which was associated with upregulated expression of ATP-binding cassette A1/G1 (ABCA1/G1), liver X receptor-α (LXRα), and peroxisome proliferator-activated receptor-γ (PPARγ). Unexpectedly, the diterpenoids C069002 and C069004 failed to enhance the mRNA transcription of the ABCG1 gene in macrophage-derived foam cells induced by ox-LDL. To evaluate the effects of diterpenoids on macrophage foam cell formation and determine the underlying mechanism, two drugs (lovastatin and rosiglitazone) were used as positive controls. Although both drugs could reduce macrophage foam cell formation and promote cholesterol efflux, they each had distinctive abilities to modulate the expression of cholesterol efflux-related genes. In contrast to lovastatin, rosiglitazone showed a similar influence on the expression of cholesterol efflux-related genes (including ABCA1, LXRα, and PPARγ) as the diterpenoids regardless of the presence or absence of ox-LDL, implying a similar mechanism by which they may exert atheroprotective effects. Conclusion: Our research indicates that diterpenoids effectively inhibit ox-LDL-induced macrophage foam cell formation by promoting cholesterol efflux from macrophages via the PPARγ-LXRα-ABCA1 pathway. Further investigation of diterpenoids as potential drugs for the treatment of atherosclerosis is warranted. Frontiers Media S.A. 2023-01-12 /pmc/articles/PMC9877220/ /pubmed/36713845 http://dx.doi.org/10.3389/fphar.2023.1066758 Text en Copyright © 2023 Zhang, Wu, Shi, Ma, Fang, Feng, Zhao, Zhang, Huang, Xu, Xiao, Cao and Ji. 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 Pharmacology
Zhang, Cheng
Wu, Xuewen
Shi, Pengmin
Ma, Hongyu
Fang, Fei
Feng, Qianlang
Zhao, Shuang
Zhang, Ruipu
Huang, Jinyuan
Xu, Xinting
Xiao, Weilie
Cao, Guang
Ji, Xu
Diterpenoids inhibit ox-LDL-induced foam cell formation in RAW264.7 cells by promoting ABCA1 mediated cholesterol efflux
title Diterpenoids inhibit ox-LDL-induced foam cell formation in RAW264.7 cells by promoting ABCA1 mediated cholesterol efflux
title_full Diterpenoids inhibit ox-LDL-induced foam cell formation in RAW264.7 cells by promoting ABCA1 mediated cholesterol efflux
title_fullStr Diterpenoids inhibit ox-LDL-induced foam cell formation in RAW264.7 cells by promoting ABCA1 mediated cholesterol efflux
title_full_unstemmed Diterpenoids inhibit ox-LDL-induced foam cell formation in RAW264.7 cells by promoting ABCA1 mediated cholesterol efflux
title_short Diterpenoids inhibit ox-LDL-induced foam cell formation in RAW264.7 cells by promoting ABCA1 mediated cholesterol efflux
title_sort diterpenoids inhibit ox-ldl-induced foam cell formation in raw264.7 cells by promoting abca1 mediated cholesterol efflux
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9877220/
https://www.ncbi.nlm.nih.gov/pubmed/36713845
http://dx.doi.org/10.3389/fphar.2023.1066758
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