Skip to main content

Advertisement

SpringerLink
Log in

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

  • Original Article
  • Published:
Inflammation Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. Abderrazak, A., D. Couchie, D.F. Mahmood, R. Elhage, C. Vindis, M. Laffargue, V. Mateo, et al. 2015. Anti-inflammatory and antiatherogenic effects of the NLRP3 inflammasome inhibitor arglabin in ApoE2.Ki mice fed a high-fat diet. Circulation 131 (12): 1061–1070. https://doi.org/10.1161/CIRCULATIONAHA.114.013730.

    Article  CAS  PubMed  Google Scholar 

  2. Aviram, M. 2011. Atherosclerosis: Cell biology and lipoproteins--inflammation and oxidative stress in atherogenesis: Protective role for paraoxonases. Current Opinion in Lipidology 22 (3): 243–244. https://doi.org/10.1097/MOL.0b013e3283474beb.

    Article  CAS  PubMed  Google Scholar 

  3. Bhansali, S., S. Khatri, and V. Dhawan. 2019. Terminalia Arjuna bark extract impedes foam cell formation and promotes apoptosis in ox-LDL-stimulated macrophages by enhancing UPR-CHOP pathway. Lipids in Health and Disease 18 (1): 195. https://doi.org/10.1186/s12944-019-1119-z.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Bhaskar, S., P.R. Sudhakaran, and A. Helen. 2016. Quercetin attenuates atherosclerotic inflammation and adhesion molecule expression by modulating TLR-NF-kappaB signaling pathway. Cellular Immunology 310: 131–140. https://doi.org/10.1016/j.cellimm.2016.08.011.

    Article  CAS  PubMed  Google Scholar 

  5. Bryk, D., W. Olejarz, and D. Zapolska-Downar. 2017. The role of oxidative stress and NADPH oxidase in the pathogenesis of atherosclerosis. Postȩpy Higieny i Medycyny Doświadczalnej (Online) 71 (0): 57–68. https://doi.org/10.5604/17322693.1229823.

    Article  Google Scholar 

  6. 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.

    Article  CAS  Google Scholar 

  7. Chen, D.D., L.L. Hui, X.C. Zhang, and Q. Chang. 2018. NEAT1 contributes to ox-LDL-induced inflammation and oxidative stress in macrophages through inhibiting miR-128. Journal of Cellular Biochemistry. https://doi.org/10.1002/jcb.27541.

  8. Chen, K.C., and S.H. Juo. 2012. MicroRNAs in atherosclerosis. The Kaohsiung Journal of Medical Sciences 28 (12): 631–640. https://doi.org/10.1016/j.kjms.2012.04.001.

    Article  CAS  PubMed  Google Scholar 

  9. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Farhat, N., N. Thorin-Trescases, M. Mamarbachi, L. Villeneuve, C. Yu, C. Martel, N. Duquette, M. Gayda, A. Nigam, M. Juneau, B.G. Allen, and E. Thorin. 2013. Angiopoietin-like 2 promotes Atherogenesis in mice. Journal of the American Heart Association 2 (3): 13. https://doi.org/10.1161/jaha.113.000201.

    Article  Google Scholar 

  11. Gan, L., Z. Liu, F. Feng, T. Wu, D. Luo, C. Hu, and C. Sun. 2018. Foxc2 coordinates inflammation and browning of white adipose by leptin-STAT3-PRDM16 signal in mice. International Journal of Obesity 42 (2): 252–259. https://doi.org/10.1038/ijo.2017.208.

    Article  CAS  PubMed  Google Scholar 

  12. Gan, L., Z.J. Liu, W. Jin, Z.J. Zhou, and C. Sun. 2015. Foxc2 enhances proliferation and inhibits apoptosis through activating Akt/mTORC1 signaling pathway in mouse preadipocytes. Journal of Lipid Research 56 (8): 1471–1480. https://doi.org/10.1194/jlr.M057679.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Guo, C.X., R. Ma, X.Y. Liu, T. Chen, Y. Li, Y. Yu, J.C. Duan, X.Q. Zhou, Y.B. Li, and Z.W. Sun. 2018. Silica nanoparticles promote oxLDL-induced macrophage lipid accumulation and apoptosis via endoplasmic reticulum stress signaling. Science of the Total Environment 631-632: 570–579. https://doi.org/10.1016/j.scitotenv.2018.02.312.

    Article  CAS  PubMed  Google Scholar 

  14. 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.

    CAS  PubMed  Google Scholar 

  15. Jia, H., H. Li, Y. Zhang, C. Li, Y. Hu, and C. Xia. 2015. Association between red blood cell distribution width (RDW) and carotid artery atherosclerosis (CAS) in patients with primary ischemic stroke. Archives of Gerontology and Geriatrics 61 (1): 72–75. https://doi.org/10.1016/j.archger.2015.04.005.

    Article  PubMed  Google Scholar 

  16. Jia, S.J., K.Q. Gao, and M. Zhao. 2017. Epigenetic regulation in monocyte/macrophage: A key player during atherosclerosis. Cardiovascular Therapeutics 35 (3). https://doi.org/10.1111/1755-5922.12262.

  17. Li, D., and Y. Tan. 2019. TIPE2 suppresses atherosclerosis by exerting a protective effect on macrophages via the inhibition of the Akt signaling pathway. Experimental and Therapeutic Medicine 17 (4): 2937–2944. https://doi.org/10.3892/etm.2019.7316.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Li, E., T. Wang, F. Wang, T. Wang, L.Q. Sun, L. Li, S.H. Niu, and J.Y. Zhang. 2015. FGF21 protects against ox-LDL induced apoptosis through suppressing CHOP expression in THP1 macrophage derived foam cells. BMC Cardiovascular Disorders 15: 80. https://doi.org/10.1186/s12872-015-0077-2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Libby, P., P.M. Ridker, and G.K. Hansson. 2011. Progress and challenges in translating the biology of atherosclerosis. Nature 473 (7347): 317–325. https://doi.org/10.1038/nature10146.

    Article  CAS  PubMed  Google Scholar 

  20. Liu, J.Y., S. Liang, Z. Du, J.Y. Zhang, B.Y. Sun, T. Zhao, X.Z. Yang, Y.F. Shi, J.C. Duan, and Z.W. Sun. 2019. PM2.5 aggravates the lipid accumulation, mitochondrial damage and apoptosis in macrophage foam cells. Environmental Pollution 249: 482–490. https://doi.org/10.1016/j.envpol.2019.03.045.

    Article  CAS  PubMed  Google Scholar 

  21. Long, L., and Y. Song. 2018. Dietary ellagic acid is protective for atherosclerosis. International Journal of Cardiology 256: 12. https://doi.org/10.1016/j.ijcard.2017.12.094.

    Article  PubMed  Google Scholar 

  22. Meng, F., J. Yan, Q. Ma, Y. Jiao, L. Han, J. Xu, F. Yang, and J. Liu. 2018. Expression status and clinical significance of lncRNA APPAT in the progression of atherosclerosis. PeerJ 6: e4246. https://doi.org/10.7717/peerj.4246.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Moore, K.J., and I. Tabas. 2011. Macrophages in the pathogenesis of atherosclerosis. Cell 145 (3): 341–355. https://doi.org/10.1016/j.cell.2011.04.005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Pan, M.S., Y.J. Huo, C.T. Wang, Y.H. Zhang, Z.Y. Dai, and B. Li. 2019. Positively charged peptides from casein hydrolysate show strong inhibitory effects on LDL oxidation and cellular lipid accumulation in Raw264.7 cells. International Dairy Journal 91: 119–128. https://doi.org/10.1016/j.idairyj.2018.09.011.

    Article  CAS  Google Scholar 

  25. Peng, S., L.W. Xu, X.Y. Che, Q.Q. Xiao, J. Pu, Q. Shao, and B. He. 2018. Atorvastatin inhibits inflammatory response, attenuates lipid deposition, and improves the stability of vulnerable atherosclerotic plaques by modulating autophagy. Frontiers in Pharmacology 9: 17. https://doi.org/10.3389/fphar.2018.00438.

    Article  CAS  Google Scholar 

  26. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Rios, F.J., M. Gidlund, and S. Jancar. 2011. Pivotal role for platelet-activating factor receptor in CD36 expression and oxLDL uptake by human monocytes/macrophages. Cellular Physiology and Biochemistry 27 (3–4): 363–372. https://doi.org/10.1159/000327962.

    Article  CAS  PubMed  Google Scholar 

  28. 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.

    Article  CAS  Google Scholar 

  29. Seimon, T., and I. Tabas. 2009. Mechanisms and consequences of macrophage apoptosis in atherosclerosis. Journal of Lipid Research 50 (Suppl): S382–S387. https://doi.org/10.1194/jlr.R800032-JLR200.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. 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.

    Article  CAS  PubMed  Google Scholar 

  31. Wang, J.C., and M. Bennett. 2012. Aging and atherosclerosis: Mechanisms, functional consequences, and potential therapeutics for cellular senescence. Circulation Research 111 (2): 245–259. https://doi.org/10.1161/CIRCRESAHA.111.261388.

    Article  CAS  PubMed  Google Scholar 

  32. 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.

    Article  CAS  PubMed  Google Scholar 

  33. Yan, L., Z. Liu, H. Yin, Z. Guo, and Q. Luo. 2019. Silencing of MEG3 inhibited ox-LDL-induced inflammation and apoptosis in macrophages via modulation of the MEG3/miR-204/CDKN2A regulatory axis. Cell Biology International 43 (4): 409–420. https://doi.org/10.1002/cbin.11105.

    Article  CAS  PubMed  Google Scholar 

  34. 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.

  35. Zhang, C., J. Chen, Y. Liu, and D. Xu. 2019. Sialic acid metabolism as a potential therapeutic target of atherosclerosis. Lipids in Health and Disease 18 (1): 173. https://doi.org/10.1186/s12944-019-1113-5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Zhang, E., and Y. Wu. 2013. MicroRNAs: Important modulators of oxLDL-mediated signaling in atherosclerosis. Journal of Atherosclerosis and Thrombosis 20 (3): 215–227. https://doi.org/10.5551/jat.15180.

    Article  CAS  PubMed  Google Scholar 

  37. 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.

    Article  CAS  PubMed  Google Scholar 

  38. Zheng, G.L., H.Z. Li, T. Zhang, L.B. Yang, S.T. Yao, S.H. Chen, M.C. Zheng, Q. Zhao, and H. Tian. 2018. Irisin protects macrophages from oxidized low density lipoprotein-induced apoptosis by inhibiting the endoplasmic reticulum stress pathway. Saudi Journal of Biological Sciences 25 (5): 849–857. https://doi.org/10.1016/j.sjbs.2017.08.018.

    Article  CAS  PubMed  Google Scholar 

  39. Zhou, P.L., M. Li, X.W. Han, Y.H. Bi, W.G. Zhang, Z.Y. Wu, and G. Wu. 2019. Perilipin 5 deficiency promotes atherosclerosis progression through accelerating inflammation, apoptosis, and oxidative stress. Journal of Cellular Biochemistry 120 (11): 19107–19123. https://doi.org/10.1002/jcb.29238.

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

The present study was supported by the Natural Science Foundation of Hunan Province, China (Grant No. 14JJ7006), the Science and Technology Innovation Planning Project of Hunan Province, China (Grant No. 2017SK50104), and the Scientific Research Project of Hunan Health Commission (Grant No. 20201228).

Author information

Author notes

  1. Liu Yang and Tie Li contributed equally to this work.

Authors and Affiliations

  1. International Medical Center, Geriatric Department, National clinical research center of geriatric diseases, Xiangya Hospital of Central South University, 87 Xiangya Road, Changsha, 410008, Hunan, China

    Liu Yang

  2. Department of Cardiology, Changsha Central Hospital, Changsha, 410000, Hunan, China

    Tie Li

  3. Department of Cardiology, Xiangya Hospital of Central South University, Changsha, 410008, Hunan, China

    Lihuang Zha

Authors
  1. Liu Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tie Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lihuang Zha
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Liu Yang.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yang, L., Li, T. & Zha, L. Foxc2 Alleviates Ox-LDL-Induced Lipid Accumulation, Inflammation, and Apoptosis of Macrophage via Regulating the Expression of Angptl2. Inflammation 43, 1397–1410 (2020). https://doi.org/10.1007/s10753-020-01217-w

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10753-020-01217-w

Key Words

Search

Navigation