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Published in: Inflammation 4/2020

01-08-2020 | Arterial Occlusive Disease | Original Article

Foxc2 Alleviates Ox-LDL-Induced Lipid Accumulation, Inflammation, and Apoptosis of Macrophage via Regulating the Expression of Angptl2

Authors: Liu Yang, Tie Li, Lihuang Zha

Published in: Inflammation | Issue 4/2020

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Abstract

The present study aimed to investigate the role of Forkhead box protein C2 (Foxc2) in oxidized low-density lipoprotein (ox-LDL)-induced macrophages and identify the potential mechanisms. RAW264.7 cells, the murine macrophage cell line, were stimulated by ox-LDL, and cell proliferation was examined. The levels of inflammation- and oxidative stress-related markers were detected using kits after induction with ox-LDL. Subsequently, the expression of Foxc2 was measured using Western blotting. After transfection with Foxc2 pcDNA3.1, intracellular lipid droplets were examined using oil red O staining. The levels of total cholesterol (TC), free cholesterol (FC), inflammatory cytokines, and oxidative stress markers were determined. Moreover, apoptosis of RAW264.7 cells was detected using flow cytometry, and apoptosis-related proteins were measured using Western blotting. Angiopoietin-like protein 2 (Angptl2) was predicted as a target gene of Foxc2. Therefore, the expression of Angptl2 was examined after Foxc2 overexpression in ox-LDL-induced RAW264.7 cells. Then, the changes of intracellular lipid droplets, TC, FC, inflammatory cytokines, oxidative stress factors, and cell apoptosis were detected after Angptl2 overexpression or co-transfection with Foxc2 and Angptl2 pcDNA3.1. The results revealed that ox-LDL induction inhibited proliferation of RAW264.7 cells and promoted the release of inflammatory factors. Importantly, the expression of Foxc2 was obviously decreased after stimulation by ox-LDL. Foxc2 overexpression suppressed lipid accumulation, TC, FC levels, inflammation, oxidative stress, and apoptosis induced by ox-LDL, whereas these inhibitory effects were relieved after co-transfection with Angptl2 pcDNA3.1. These findings demonstrated that Foxc2 can alleviate ox-LDL-induced lipid accumulation, inflammation, and apoptosis of macrophage via regulating the expression of Angptl2.
Literature
6.
go back to reference Caland, L., P. Labbe, M. Mamarbachi, L. Villeneuve, G. Ferbeyre, P.E. Noly, M. Carrier, N. Thorin-Trescases, and E. Thorin. 2019. Knockdown of angiopoietin-like 2 induces clearance of vascular endothelial senescent cells by apoptosis, promotes endothelial repair and slows atherogenesis in mice. Aging (Albany NY) 11 (11): 3832–3850. https://doi.org/10.18632/aging.102020.CrossRef Caland, L., P. Labbe, M. Mamarbachi, L. Villeneuve, G. Ferbeyre, P.E. Noly, M. Carrier, N. Thorin-Trescases, and E. Thorin. 2019. Knockdown of angiopoietin-like 2 induces clearance of vascular endothelial senescent cells by apoptosis, promotes endothelial repair and slows atherogenesis in mice. Aging (Albany NY) 11 (11): 3832–3850. https://​doi.​org/​10.​18632/​aging.​102020.CrossRef
7.
9.
go back to reference Duewell, P., H. Kono, K.J. Rayner, C.M. Sirois, G. Vladimer, F.G. Bauernfeind, G.S. Abela, L. Franchi, G. Nuñez, M. Schnurr, T. Espevik, E. Lien, K.A. Fitzgerald, K.L. Rock, K.J. Moore, S.D. Wright, V. Hornung, and E. Latz. 2010. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature 464 (7293): 1357–1361. https://doi.org/10.1038/nature08938.CrossRefPubMedPubMedCentral Duewell, P., H. Kono, K.J. Rayner, C.M. Sirois, G. Vladimer, F.G. Bauernfeind, G.S. Abela, L. Franchi, G. Nuñez, M. Schnurr, T. Espevik, E. Lien, K.A. Fitzgerald, K.L. Rock, K.J. Moore, S.D. Wright, V. Hornung, and E. Latz. 2010. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature 464 (7293): 1357–1361. https://​doi.​org/​10.​1038/​nature08938.CrossRefPubMedPubMedCentral
10.
14.
go back to reference Iida, K., H. Koseki, H. Kakinuma, N. Kato, Y. Mizutani-Koseki, H. Ohuchi, H. Yoshioka, S. Noji, K. Kawamura, Y. Kataoka, F. Ueno, M. Taniguchi, N. Yoshida, T. Sugiyama, and N. Miura. 1997. Essential roles of the winged helix transcription factor MFH-1 in aortic arch patterning and skeletogenesis. Development 124 (22): 4627–4638.PubMed Iida, K., H. Koseki, H. Kakinuma, N. Kato, Y. Mizutani-Koseki, H. Ohuchi, H. Yoshioka, S. Noji, K. Kawamura, Y. Kataoka, F. Ueno, M. Taniguchi, N. Yoshida, T. Sugiyama, and N. Miura. 1997. Essential roles of the winged helix transcription factor MFH-1 in aortic arch patterning and skeletogenesis. Development 124 (22): 4627–4638.PubMed
25.
26.
go back to reference Rahman, K., Y. Vengrenyuk, S.A. Ramsey, N.R. Vila, N.M. Girgis, J. Liu, V. Gusarova, J. Gromada, A. Weinstock, K.J. Moore, P. Loke, and E.A. Fisher. 2017. Inflammatory Ly6Chi monocytes and their conversion to M2 macrophages drive atherosclerosis regression. The Journal of Clinical Investigation 127 (8): 2904–2915. https://doi.org/10.1172/JCI75005.CrossRefPubMedPubMedCentral Rahman, K., Y. Vengrenyuk, S.A. Ramsey, N.R. Vila, N.M. Girgis, J. Liu, V. Gusarova, J. Gromada, A. Weinstock, K.J. Moore, P. Loke, and E.A. Fisher. 2017. Inflammatory Ly6Chi monocytes and their conversion to M2 macrophages drive atherosclerosis regression. The Journal of Clinical Investigation 127 (8): 2904–2915. https://​doi.​org/​10.​1172/​JCI75005.CrossRefPubMedPubMedCentral
28.
go back to reference Sasaki, Y., M. Ohta, D. Desai, J.L. Figueiredo, M.C. Whelan, T. Sugano, M. Yamabi, W. Yano, T. Faits, K. Yabusaki, H. Zhang, A.K. Mlynarchik, K. Inoue, K. Mizuno, and M. Aikawa. 2015. Angiopoietin like protein 2 (ANGPTL2) promotes adipose tissue macrophage and T lymphocyte accumulation and leads to insulin resistance. PLoS One 10 (7): 18. https://doi.org/10.1371/journal.pone.0131176.CrossRef Sasaki, Y., M. Ohta, D. Desai, J.L. Figueiredo, M.C. Whelan, T. Sugano, M. Yamabi, W. Yano, T. Faits, K. Yabusaki, H. Zhang, A.K. Mlynarchik, K. Inoue, K. Mizuno, and M. Aikawa. 2015. Angiopoietin like protein 2 (ANGPTL2) promotes adipose tissue macrophage and T lymphocyte accumulation and leads to insulin resistance. PLoS One 10 (7): 18. https://​doi.​org/​10.​1371/​journal.​pone.​0131176.CrossRef
30.
go back to reference Tabata, M., T. Kadomatsu, S. Fukuhara, K. Miyata, Y. Ito, M. Endo, T. Urano, H.J. Zhu, H. Tsukano, H. Tazume, K. Kaikita, K. Miyashita, T. Iwawaki, M. Shimabukuro, K. Sakaguchi, T. Ito, N. Nakagata, T. Yamada, H. Katagiri, M. Kasuga, Y. Ando, H. Ogawa, N. Mochizuki, H. Itoh, T. Suda, and Y. Oike. 2009. Angiopoietin-like protein 2 promotes chronic adipose tissue inflammation and obesity-related systemic insulin resistance. Cell Metabolism 10 (3): 178–188. https://doi.org/10.1016/j.cmet.2009.08.003.CrossRefPubMed Tabata, M., T. Kadomatsu, S. Fukuhara, K. Miyata, Y. Ito, M. Endo, T. Urano, H.J. Zhu, H. Tsukano, H. Tazume, K. Kaikita, K. Miyashita, T. Iwawaki, M. Shimabukuro, K. Sakaguchi, T. Ito, N. Nakagata, T. Yamada, H. Katagiri, M. Kasuga, Y. Ando, H. Ogawa, N. Mochizuki, H. Itoh, T. Suda, and Y. Oike. 2009. Angiopoietin-like protein 2 promotes chronic adipose tissue inflammation and obesity-related systemic insulin resistance. Cell Metabolism 10 (3): 178–188. https://​doi.​org/​10.​1016/​j.​cmet.​2009.​08.​003.CrossRefPubMed
32.
go back to reference Xu, Y.J., P. Li, L. Zheng, F.X. Guo, C.M. Kang, L. Ding, B.M. Xu, et al. 2019. Forkhead box C2 attenuates lipopolysaccharide-induced cell adhesion via suppression of intercellular adhesion Molecule-1 expression in human umbilical vein endothelial cells. DNA and Cell Biology 38 (6): 583–591. https://doi.org/10.1089/dna.2019.4663.CrossRefPubMed Xu, Y.J., P. Li, L. Zheng, F.X. Guo, C.M. Kang, L. Ding, B.M. Xu, et al. 2019. Forkhead box C2 attenuates lipopolysaccharide-induced cell adhesion via suppression of intercellular adhesion Molecule-1 expression in human umbilical vein endothelial cells. DNA and Cell Biology 38 (6): 583–591. https://​doi.​org/​10.​1089/​dna.​2019.​4663.CrossRefPubMed
34.
go back to reference Zahid, M. K., M. Rogowski, C. Ponce, M. Choudhury, N. Moustaid-Moussa, and S. M. Rahman. CCAAT/enhancer-binding protein beta (C/EBP beta) knockdown reduces inflammation, ER stress, and apoptosis, and promotes autophagy in oxLDL-treated RAW264.7 macrophage cells. Molecular and Cellular Biochemistry:13. https://doi.org/10.1007/s11010-019-03642-4. Zahid, M. K., M. Rogowski, C. Ponce, M. Choudhury, N. Moustaid-Moussa, and S. M. Rahman. CCAAT/enhancer-binding protein beta (C/EBP beta) knockdown reduces inflammation, ER stress, and apoptosis, and promotes autophagy in oxLDL-treated RAW264.7 macrophage cells. Molecular and Cellular Biochemistry:13. https://​doi.​org/​10.​1007/​s11010-019-03642-4.
37.
go back to reference Zhang, Q., J. Hu, Y. Wu, H. Luo, W. Meng, B. Xiao, X. Xiao, Z. Zhou, and F. Liu. 2019. Rheb (Ras homolog enriched in brain 1) deficiency in mature macrophages prevents atherosclerosis by repressing macrophage proliferation, inflammation, and lipid uptake. Arteriosclerosis, Thrombosis, and Vascular Biology 39 (9): 1787–1801. https://doi.org/10.1161/ATVBAHA.119.312870.CrossRefPubMed Zhang, Q., J. Hu, Y. Wu, H. Luo, W. Meng, B. Xiao, X. Xiao, Z. Zhou, and F. Liu. 2019. Rheb (Ras homolog enriched in brain 1) deficiency in mature macrophages prevents atherosclerosis by repressing macrophage proliferation, inflammation, and lipid uptake. Arteriosclerosis, Thrombosis, and Vascular Biology 39 (9): 1787–1801. https://​doi.​org/​10.​1161/​ATVBAHA.​119.​312870.CrossRefPubMed
39.
Metadata
Title
Foxc2 Alleviates Ox-LDL-Induced Lipid Accumulation, Inflammation, and Apoptosis of Macrophage via Regulating the Expression of Angptl2
Authors
Liu Yang
Tie Li
Lihuang Zha
Publication date
01-08-2020
Publisher
Springer US
Published in
Inflammation / Issue 4/2020
Print ISSN: 0360-3997
Electronic ISSN: 1573-2576
DOI
https://doi.org/10.1007/s10753-020-01217-w

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