Exosomal MALAT1 derived from ox-LDL-treated endothelial cells induce neutrophil extracellular traps to aggravate atherosclerosis
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Hailai Gao
und
Xiao Liang
Abstract
The objective of this study was to reveal a novel mechanism underlying the progression of atherosclerosis (AS) associated with endothelial cells (ECs) and neutrophils. Transmission electron microscopy (TEM) and nanoparticle tracking analysis (NTA) were used to observe the morphology and particle size of isolated exosomes. Western blotting was applied to examine exosomal markers, while the expression of metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) was measured by quantitative real-time polymerase chain reaction (qRT-PCR). The production of inflammatory cytokines and reactive oxygen species (ROS) was determined by an enzyme-linked immunosorbent assay (ELISA) and a dichloro-dihydro-fluorescein diacetate (DCFH-DA) assay. Circulating neutrophil extracellular traps (NETs) were represented by myeloperoxidase (MPO)-DNA complexes. NETs formation was assessed using immunofluorescence microscopy. Atherosclerotic lesion development was measured by Oil Red O (ORO) staining. In the results, MALAT1 expression was increased in exosomes extracted from oxidized low-density lipoprotein (ox-LDL)-treated human umbilical vein endothelial cells (HUVECs). When co-cultured with human neutrophils, exosomes derived from ox-LDL-treated HUVECs were revealed to promote NETs formation, which was mediated by exosomal MALAT1. Furthermore, ox-LDL-treated HUVECs-derived exosomes were demonstrated to trigger hyperlipidemia, inflammatory response and NETs release in a mouse model of AS. In conclusion, exosomal MALAT1 derived from ox-LDL-treated ECs initiated NETs formation, which in turn deteriorated AS.
Funding source: Nature Scientific Foundation of Heilongjiang Province
Award Identifier / Grant number: H201442
Funding source: Heilongjiang Provincial Education Department
Award Identifier / Grant number: 12541450
Funding statement: This study was supported by the Nature Scientific Foundation of Heilongjiang Province (H201442) and the Heilongjiang Provincial Education Department (12541450).
Conflict of interest statement: The authors declare no conflict of interest.
References
Carmona-Rivera, C., Zhao, W., Yalavarthi, S., and Kaplan, M.J. (2015). Neutrophil extracellular traps induce endothelial dysfunction in systemic lupus erythematosus through the activation of matrix metalloproteinase-2. Ann. Rheum. Dis. 74, 1417–1424.10.1136/annrheumdis-2013-204837Suche in Google Scholar PubMed PubMed Central
Chen, L., Yang, W., Guo, Y., Chen, W., Zheng, P., Zeng, J., and Tong, W. (2017). Exosomal lncRNA GAS5 regulates the apoptosis of macrophages and vascular endothelial cells in atherosclerosis. PLoS One 12, e0185406.10.1371/journal.pone.0185406Suche in Google Scholar PubMed PubMed Central
Chun Xiang, S., Downey, G.P., Fei, Z., Koh, A.L.Y., Herman, T., and Michael, G. (2004). Rac1 is the small GTPase responsible for regulating the neutrophil chemotaxis compass. Blood 104, 3758–3765.10.1182/blood-2004-03-0781Suche in Google Scholar PubMed
Doring, Y., Soehnlein, O., and Weber, C. (2017). Neutrophil extracellular traps in atherosclerosis and atherothrombosis. Circ. Res. 120, 736–743.10.1161/CIRCRESAHA.116.309692Suche in Google Scholar PubMed
Douda, D.N., Yip, L., Khan, M.A., Grasemann, H., and Palaniyar, N. (2014). Akt is essential to induce NADPH-dependent NETosis and to switch the neutrophil death to apoptosis. Blood 123, 597–600.10.1182/blood-2013-09-526707Suche in Google Scholar PubMed
Dyer, M.R., Chen, Q., Haldeman, S., Yazdani, H., Hoffman, R., Loughran, P., Tsung, A., Zuckerbraun, B.S., Simmons, R.L., and Neal, M.D. (2018). Deep vein thrombosis in mice is regulated by platelet HMGB1 through release of neutrophil-extracellular traps and DNA. Sci. Rep. 8, 2068.10.1038/s41598-018-20479-xSuche in Google Scholar PubMed PubMed Central
Gong, W., Zhu, G., Li, J., and Yang, X. (2018). LncRNA MALAT1 promotes the apoptosis and oxidative stress of human lens epithelial cells via p38MAPK pathway in diabetic cataract. Diabetes Res. Clin. Pract. 144, 314–321.10.1016/j.diabres.2018.06.020Suche in Google Scholar PubMed
Han, X., Han, X., Wang, Z., Shen, J., and Dong, Q. (2016). HDAC9 regulates ox-LDL-induced endothelial cell apoptosis by participating in inflammatory reactions. Front. Biosci. (Landmark Ed.) 21, 907–917.10.2741/4428Suche in Google Scholar PubMed
Hergenreider, E., Heydt, S., Tréguer, K., Boettger, T., Horrevoets, A.J., Zeiher, A.M., Scheffer, M.P., Frangakis, A.S., Yin, X., Mayr, M., et al. (2012). Atheroprotective communication between endothelial cells and smooth muscle cells through miRNAs. Nat. Cell Biol. 14, 249–256.10.1038/ncb2441Suche in Google Scholar PubMed
Huang, C., Han, J., Wu, Y., Li, S., Wang, Q., Lin, W., and Zhu, J. (2018). Exosomal MALAT1 derived from oxidized low-density lipoprotein-treated endothelial cells promotes M2 macrophage polarization. Mol. Med. Rep. 18, 509–515.10.3892/mmr.2018.8982Suche in Google Scholar PubMed
Keshari, R.S., Anupam, V., Barthwal, M.K., and Madhu, D. (2013). Reactive oxygen species-induced activation of ERK and p38 MAPK mediates PMA-induced NETs release from human neutrophils. J. Cell. Biochem. 114, 532–540.10.1002/jcb.24391Suche in Google Scholar PubMed
Lawson, C., Vicencio, J.M., Yellon, D.M., and Davidson, S.M. (2016). Microvesicles and exosomes: new players in metabolic and cardiovascular disease. J. Endocrinol. 228, R57–R71.10.1530/JOE-15-0201Suche in Google Scholar PubMed
Li, H., Zhao, Q., Chang, L., Wei, C., Bei, H., Yin, Y., Chen, M., Wang, H., Liang, J., and Wu, Y. (2019). LncRNA MALAT1 modulates ox-LDL induced EndMT through the Wnt/β-catenin signaling pathway. Lipids Health Dis. 18, 62.10.1186/s12944-019-1006-7Suche in Google Scholar PubMed PubMed Central
Marin-Esteban, V., Barrientos, L., and Chollet-Martin, S. (2016). Neutrophil extracellular traps. In: Compendium of Inflammatory Diseases, M.J. Parnham, ed. (Basel: Springer Basel), pp. 962–971.10.1007/978-3-7643-8550-7_181Suche in Google Scholar
Qiu, J.J., Lin, X.J., Zheng, T.T., Tang, X.Y., Zhang, Y., and Hua, K.Q. (2019). The exosomal long noncoding RNA aHIF is upregulated in serum from patients with endometriosis and promotes angiogenesis in endometriosis. Reprod. Sci. 1933719119831775.10.1177/1933719119831775Suche in Google Scholar PubMed
Rui, Z., Xue, L., Liu, X., Wang, X., Gong, J., Yan, L., Wang, L., Yang, W., Wang, X., and Qian, L.J. (2009). Heat shock protein 70 is secreted from endothelial cells by a non-classical pathway involving exosomes. Biochem. Biophys. Res. Commun. 387, 229–233.10.1016/j.bbrc.2009.06.095Suche in Google Scholar PubMed
Sørensen, O.E. and Borregaard, N. (2016). Neutrophil extracellular traps – the dark side of neutrophils. J. Clin. Invest. 126, 1612–1620.10.1172/JCI84538Suche in Google Scholar PubMed PubMed Central
Song, Y., Yang, L., Guo, R., Lu, N., Shi, Y., and Wang, X. (2019). Long noncoding RNA MALAT1 promotes high glucose-induced human endothelial cells pyroptosis by affecting NLRP3 expression through competitively binding miR-22. Biochem. Biophys. Res. Commun. 509, 359–366.10.1016/j.bbrc.2018.12.139Suche in Google Scholar PubMed
Spitz, C., Winkels, H., Bürger, C., Weber, C., Lutgens, E., Hansson, G.K., and Gerdes, N. (2016). Regulatory T cells in atherosclerosis: critical immune regulatory function and therapeutic potential. Cell. Mol. Life Sci. 73, 901–922.10.1007/s00018-015-2080-2Suche in Google Scholar PubMed
Su, S.A., Xie, Y., Fu, Z., Wang, Y., Wang, J.A., and Xiang, M. (2017). Emerging role of exosome-mediated intercellular communication in vascular remodeling. Oncotarget 8, 25700–25712.10.18632/oncotarget.14878Suche in Google Scholar PubMed PubMed Central
Tang, Y., Xiao, G., Chen, Y., and Deng, Y. (2018). LncRNA MALAT1 promotes migration and invasion of non-small-cell lung cancer by targeting miR-206 and activating Akt/mTOR signaling. Anticancer Drugs 29, 725–735.10.1097/CAD.0000000000000650Suche in Google Scholar PubMed
Woollard, K.J. (2013). Immunological aspects of atherosclerosis. Clin. Sci. (Lond.) 125, 221–235.10.1042/CS20120576Suche in Google Scholar PubMed
Xiao, J. and Cretoiu, S. (2017). Exosomes in Cardiovascular Diseases. Adv. Exp. Med. Biol. 998, 71–88.10.1007/978-981-10-4397-0Suche in Google Scholar
Yamamoto, K., Yamada, H., Wakana, N., Kikai, M., Terada, K., Wada, N., Motoyama, S., Saburi, M., Sugimoto, T., Kami,D., et al. (2018). Augmented neutrophil extracellular traps formation promotes atherosclerosis development in socially defeated apoE-/- mice. Biochem. Biophys. Res. Commun. 500, 490–496.10.1016/j.bbrc.2018.04.115Suche in Google Scholar PubMed
Yang, H., Mohamed, A.S., and Zhou, S.H. (2012). Oxidized low density lipoprotein, stem cells, and atherosclerosis. Lipids Health Dis. 11, 85.10.1186/1476-511X-11-85Suche in Google Scholar PubMed PubMed Central
Yu, F., Lu, Z., Cai, J., Huang, K., Chen, B., Li, G., Dong, P., and Zheng, J. (2015). MALAT1 functions as a competing endogenous RNA to mediate Rac1 expression by sequestering miR-101b in liver fibrosis. Cell Cycle 14, 3885–3896.10.1080/15384101.2015.1120917Suche in Google Scholar PubMed PubMed Central
Zhang, Y., Dai, Q., Zeng, F., and Liu, H. (2018). MALAT1 promotes the proliferation and metastasis of osteosarcoma cells by activating the Rac1/JNK pathway via targeting MiR-509. Oncol. Res. doi: 10.3727/096504017X14957939026111.10.3727/096504017X14957939026111Suche in Google Scholar PubMed
©2020 Walter de Gruyter GmbH, Berlin/Boston
Artikel in diesem Heft
- Frontmatter
- Reviews
- Genetic, epigenetic and biochemical regulation of succinate dehydrogenase function
- Transport mechanism of Mycobacterium tuberculosis MmpL/S family proteins and implications in pharmaceutical targeting
- Research Articles/Short Communications
- Genes and Nucleic Acids
- LncRNA MALAT1 inhibits hypoxia/reoxygenation-induced human umbilical vein endothelial cell injury via targeting the microRNA-320a/RAC1 axis
- Protein Structure and Function
- Identification of new probe substrates for human CYP20A1
- Molecular Medicine
- Exosomal MALAT1 derived from ox-LDL-treated endothelial cells induce neutrophil extracellular traps to aggravate atherosclerosis
- Cell Biology and Signaling
- Derlin-1 functions as a growth promoter in breast cancer
- Alterations in rat adipose tissue transcriptome and proteome in response to prolonged fasting
- Long noncoding RNA Linc01296 promotes hepatocellular carcinoma development through regulation of the miR-26a/PTEN axis
- Tumor-suppressive activity of sTRAIL on circulating CD44+ cells in patients with non-small cell lung cancer
Artikel in diesem Heft
- Frontmatter
- Reviews
- Genetic, epigenetic and biochemical regulation of succinate dehydrogenase function
- Transport mechanism of Mycobacterium tuberculosis MmpL/S family proteins and implications in pharmaceutical targeting
- Research Articles/Short Communications
- Genes and Nucleic Acids
- LncRNA MALAT1 inhibits hypoxia/reoxygenation-induced human umbilical vein endothelial cell injury via targeting the microRNA-320a/RAC1 axis
- Protein Structure and Function
- Identification of new probe substrates for human CYP20A1
- Molecular Medicine
- Exosomal MALAT1 derived from ox-LDL-treated endothelial cells induce neutrophil extracellular traps to aggravate atherosclerosis
- Cell Biology and Signaling
- Derlin-1 functions as a growth promoter in breast cancer
- Alterations in rat adipose tissue transcriptome and proteome in response to prolonged fasting
- Long noncoding RNA Linc01296 promotes hepatocellular carcinoma development through regulation of the miR-26a/PTEN axis
- Tumor-suppressive activity of sTRAIL on circulating CD44+ cells in patients with non-small cell lung cancer
