Abstract
Genistein plays an important role in the prevention of atherosclerosis. However, the underlying mechanisms have not been fully investigated. In this study, human umbilical vein endothelial cells (HUVECs) were pretreated with genistein (10, 100, and 1000 nM) for 6 h and then exposed to ox-LDL (50 mg/L) for another 24 h. Results showed that ox-LDL induced the expressions of E-selectin, P-selectin, monocyte chemotactic protein-1, interleukin-8, vascular adhesion molecule-1, and intercellular adhesion molecule-1, which were counteracted by genistein. The inhibitory effect was further enhanced with the augment of genistein (10, 100, and 1000 nM). Further analyses demonstrated the effect of genistein was associated with reducing miR-155 and elevating SOCS1, and miR-155 mimics or SOCS1 siRNA acted similarly in genistein ameliorating inflammation. Moreover, the effect of genistein was accompanied with the inhibition of the NF-ĸB signaling pathway. The present study indicates that genistein could reverse ox-LDL-induced inflammation through miR-155/SOCS1-mediated repression of the NF-ĸB signaling pathway in HUVECs.
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Castellon, X., and V. Bogdanova. 2016. Chronic inflammatory diseases and endothelial dysfunction. Aging Dis 7 (1): 81–89.
Gimbrone, M.A. Jr., and G. García-Cardeña. 2016. Endothelial cell dysfunction and the pathobiology of atherosclerosis. Circulation Research 118 (4): 620–636.
Soeki, T., and M. Sata. 2016. Inflammatory biomarkers and atherosclerosis. International Heart Journal 57 (2): 134–139.
Taleb, S. 2016. Inflammation in atherosclerosis. Archives of Cardiovascular Diseases 109 (12): 708–715.
Tousoulis, D., E. Oikonomou, E.K. Economou, F. Crea, and J.C. Kaski. 2016. Inflammatory cytokines in atherosclerosis: current therapeutic approaches. European Heart Journal 37 (22): 1723–1732.
Goya, L., M.A. Martín, B. Sarriá, S. Ramos, R. Mateos, and L. Bravo. 2016. Effect of cocoa and its flavonoids on biomarkers of inflammation: studies of cell culture, animals and humans. Nutrients 8 (4): 212.
Gupta, S.K., S. Dongare, R. Mathur, I.R. Mohanty, S. Srivastava, S. Mathur, and T.C. Nag. 2015. Genistein ameliorates cardiac inflammation and oxidative stress in streptozotocin-induced diabetic cardiomyopathy in rats. Molecular and Cellular Biochemistry 408 (1–2): 63–72.
Ji, G., Y. Zhang, Q. Yang, S. Cheng, J. Hao, X. Zhao, and Z. Jiang. 2012. Genistein suppresses LPS-induced inflammatory response through inhibiting NF-ĸB following AMP kinase activation in RAW 264.7 macrophages. PloS One 7 (12): e53101.
Liu, X.J., H.R. Bao, X.L. Zeng, and J.M. Wei. 2016. Effects of resveratrol and genistein on nuclear factor-ĸB, tumor necrosis factor-α and matrix metalloproteinase-9 in patients with chronic obstructive pulmonary disease. Molecular Medicine Reports 13 (5): 4266–4272.
Dragone, T., A. Cianciulli, R. Calvello, C. Porro, T. Trotta, and M.A. Panaro. 2014. Resveratrol counteracts lipopolysaccharide mediated microglial inflammation by modulating a SOCS-1 dependent signaling pathway. Toxicology In Vitro 28 (6): 1126–1135.
Liu, X., J. Li, X. Peng, B. Lv, P. Wang, X. Zhao, and B. Yu. 2016. Geraniin inhibits LPS-induced THP-1 macrophages switching to M1 phenotype via SOCS1/NF-κB pathway. Inflammation 39 (4): 1421–1433.
Ortiz-Muñoz, G., J.L. Martin-Ventura, P. Hernandez-Vargas, B. Mallavia, V. Lopez-Parra, O. Lopez-Franco, B. Muñoz-Garcia, et al. 2009. Suppressors of cytokine signaling modulate JAK/STAT-mediated cell responses during atherosclerosis. Arteriosclerosis, Thrombosis, and Vascular Biology 29 (4): 525–531.
Maine, G.N., X. Mao, C.M. Komarck, and E. Burstein. 2007. COMMD1 promotes the ubiquitination of NF-kappa B subunits through a cullin-containing ubiquitin ligase. The EMBO Journal 26 (2): 436–447.
Oh, J., S.H. Kim, S. Ahn, and C.E. Lee. 2012. Suppressors of cytokine signaling promote Fas-induced apoptosis through downregulation of NF-ĸB and mitochondrial Bfl-1 in leukemic T cells. Journal of Immunology 189 (12): 5561–5571.
Schweitzer, K., and M. Naumann. 2015. CSN-associated USP48 confers stability to nuclear NF-ĸB/RelA by trimming K48-linked Ub-chains. Biochimica et Biophysica Acta 1853 (2): 453–469.
Du, F., F. Yu, Y. Wang, Y. Hui, K. Carnevale, M. Fu, H. Lu, et al. 2014. MicroRNA-155 deficiency results in decreased macrophage inflammation and attenuated atherogenesis in apolipoprotein E-deficient mice. Arteriosclerosis, Thrombosis, and Vascular Biology 34 (4): 759–767.
Liu, Y., Q. Pan, Y. Zhao, C. He, K. Bi, Y. Chen, B. Zhao, et al. 2015. MicroRNA-155 regulates ROS production, NO generation, apoptosis and multiple functions of human brain microvessel endothelial cells under physiological and pathological conditions. Journal of Cellular Biochemistry 116 (12): 2870–2881.
Nazari-Jahantigh, M., Y. Wei, H. Noels, S. Akhtar, Z. Zhou, R.R. Koenen, K. Heyll, et al. 2012. MicroRNA-155 promotes atherosclerosis by repressing Bcl6 in macrophages. The Journal of Clinical Investigation 122 (11): 4190–4202.
Sun, X., N. Belkin, and M.W. Feinberg. 2013. Endothelial microRNAs and atherosclerosis. Current Atherosclerosis Reports 15 (12): 372.
Tan, Y., J. Yang, K. Xiang, Q. Tan, and Q. Guo. 2015. Suppression of microRNA-155 attenuates neuropathic pain by regulating SOCS1 signaling pathway. Neurochemical Research 40 (3): 550–560.
Yang, Y., L. Yang, X. Liang, and G. Zhu. 2015. MicroRNA-155 promotes atherosclerosis inflammation via targeting SOCS1. Cellular Physiology and Biochemistry 36 (4): 1371–1381.
Sandoval, M.J., P.H. Cutini, M.B. Rauschemberger, and V.L. Massheimer. 2010. The soyabean isoflavone genistein modulates endothelial cell behavior. British Journal of Nutrition 104 (2): 171–179.
Zhang, H.P., F.L. Zheng, J.H. Zhao, D.X. Guo, and X.L. Chen. 2013. Genistein inhibits ox-LDL-induced VCAM-1, ICAM-1 and MCP-1 expression of HUVECs through heme oxygenase-1. Archives of Medical Research 44 (1): 13–20.
Du, J., Y. Huang, H. Yan, Q. Zhang, M. Zhao, M. Zhu, J. Liu, et al. 2014. Hydrogen sulfide suppresses oxidized low-density lipoprotein (ox-LDL)-stimulated monocyte chemoattractant protein 1 generation from macrophages via the nuclear factor ĸB (NF-ĸB) pathway. The Journal of Biological Chemistry 289 (14): 9741–9753.
Huang, C.S., A.H. Lin, T.C. Yang, K.L. Liu, H.W. Chen, and C.K. Lii. 2015. Shikonin inhibits oxidized LDL-induced monocyte adhesion by suppressing NF-ĸB activation via up-regulation of PI3K/Akt/Nrf2-dependent antioxidation in EA.hy926 endothelial cells. Biochemical Pharmacology 93 (3): 352–361.
Yurdagul, A. Jr., F.J. Sulzmaier, X.L. Chen, C.B. Pattillo, D.D. Schlaepfer, and A.W. Orr. 2016. Oxidized LDL induces FAK-dependent RSK signaling to drive NF-ĸB activation and VCAM-1 expression. Journal of Cell Science 129 (8): 1580–1591.
Chung, M.H., D.H. Kim, H.K. Na, J.H. Kim, H.N. Kim, G. Haegeman, and Y.J. Surh. 2014. Genistein inhibits phorbol ester-induced NF-κB transcriptional activity and COX-2 expression by blocking the phosphorylation of p65/RelA in human mammary epithelial cells. Mutation Research 768: 74–83.
Han, S., H. Wu, W. Li, and P. Gao. 2015. Protective effects of genistein in homocysteine-induced endothelial cell inflammatory injury. Molecular and Cellular Biochemistry 403 (1–2): 43–49.
Collins, P.E., I. Mitxitorena, and R.J. Carmody. 2016. The ubiquitination of NF-κB subunits in the control of transcription. Cells 5(2): 23.
Strebovsky, J., P. Walker, R. Lang, and A.H. Dalpke. 2011. Suppressor of cytokine signaling 1 (SOCS1) limits NF-kappaB signaling by decreasing p65 stability within the cell nucleus. The FASEB Journal 25 (3): 863–874.
Andrade, C.M., M.F. Sá, and M.R. Toloi. 2012. Effects of phytoestrogens derived from soy bean on expression of adhesion molecules on HUVEC. Climacteric 15 (2): 186–194.
Babu, P.V., H. Si, Z. Fu, W. Zhen, and D. Liu. 2012. Genistein prevents hyperglycemia-induced monocyte adhesion to human aortic endothelial cells through preservation of the cAMP signaling pathway and ameliorates vascular inflammation in obese diabetic mice. The Journal of Nutrition 142 (4): 724–730.
Jia, Z., P.V. Babu, H. Si, P. Nallasamy, H. Zhu, W. Zhen, H.P. Misra, et al. 2013. Genistein inhibits TNF-α-induced endothelial inflammation through the protein kinase pathway A and improves vascular inflammation in C57BL/6 mice. International Journal of Cardiology 168 (3): 2637–2645.
Yi, L., C.Y. Chen, X. Jin, T. Zhang, Y. Zhou, Q.Y. Zhang, J.D. Zhu, et al. 2012. Differential suppression of intracellular reactive oxygen species-mediated signaling pathway in vascular endothelial cells by several subclasses of flavonoids. Biochimie 94 (9): 2035–2044.
Feinberg, M.W., and K.J. Moore. 2016. MicroRNA regulation of atherosclerosis. Circulation Research 118 (4): 703–720.
Nishiguchi, T., T. Imanishi, and T. Akasaka. 2015. MicroRNAs and cardiovascular diseases. BioMed Research International 2015: 682857.
Rao, R., P. Nagarkatti, and M. Nagarkatti. 2014. Staphylococcal enterotoxin B-induced microRNA-155 targets SOCS1 to promote acute inflammatory lung injury. Infection and Immunity 82 (7): 2971–2979.
Li, X.C., F. Tian, and F. Wang. 2013. Rheumatoid arthritis-associated microRNA-155 targets SOCS1 and upregulates TNF-α and IL-1β in PBMCs. International Journal of Molecular Sciences 14 (12): 23910–23921.
Pathak, S., A.R. Grillo, M. Scarpa, P. Brun, R. D’Incà, L. Nai, A. Banerjee, et al. 2015. MiR-155 modulates the inflammatory phenotype of intestinal myofibroblasts by targeting SOCS1 in ulcerative colitis. Experimental & Molecular Medicine 47: e164.
Ma, C., Y. Wang, A. Shen, and W. Cai. 2017. Resveratrol upregulates SOCS1 production by lipopolysaccharide stimulated RAW264.7 macrophages by inhibiting miR-155. International Journal of Molecular Medicine 39 (1): 231–237.
Pourgholi, F., M. Hajivalili, R. Razavi, S. Esmaeili, B. Baradaran, A.A. Movasaghpour, S. Sadreddini, et al. 2017. The role of M2000 as an anti-inflammatory agent in toll-like receptor 2/microRNA-155 pathway. Avicenna J Med Biotechnol 9 (1): 8–12.
Xu, H.F., X.Y. Fang, S.H. Zhu, X.H. Xu, Z.X. Zhang, Z.F. Wang, Z.Q. Zhao, et al. 2016. Glucocorticoid treatment inhibits intracerebral hemorrhage-induced inflammation by targeting the microRNA-155/SOCS-1 signaling pathway. Molecular Medicine Reports 14 (4): 3798–3804.
Wen, Y., X. Zhang, L. Dong, J. Zhao, C. Zhang, and C. Zhu. 2015. Acetylbritannilactone modulates microRNA-155-mediated inflammatory response in ischemic cerebral tissues. Molecular Medicine 18 (21): 197–209.
Park, E.J., S.Y. Park, E.H. Joe, and I. Jou. 2003. 15d-PGJ2 and rosiglitazone suppress Janus kinase-STAT inflammatory signaling through induction of suppressor of cytokine signaling 1 (SOCS1) and SOCS3 in glia. The Journal of Biological Chemistry 278 (17): 14747–14752.
Zhang, X., J. Wu, B. Ye, Q. Wang, X. Xie, and H. Shen. 2016. Protective effect of curcumin on TNBS-induced intestinal inflammation is mediated through the JAK/STAT pathway. BMC Complementary and Alternative Medicine 16 (1): 299.
Baig, M.S., S.V. Zaichick, M. Mao, A.L. de Abreu, F.R. Bakhshi, P.C. Hart, U. Saqib, et al. 2015. NOS1-derived nitric oxide promotes NF-κB transcriptional activity through inhibition of suppressor of cytokine signaling-1. The Journal of Experimental Medicine 212 (10): 1725–1738.
Filgueiras, L.R., J.O. Martins Jr., C.H. Serezani, V.L. Capelozzi, M.B. Montes, and S. Jancar. 2012. Sepsis-induced acute lung injury (ALI) is milder in diabetic rats and correlates with impaired NF-ĸB activation. PloS One 7 (9): e44987.
Serezani, C.H., C. Lewis, S. Jancar, and M. Peters-Golden. 2011. Leukotriene B4 amplifies NF-ĸB activation in mouse macrophages by reducing SOCS1 inhibition of MyD88expression. The Journal of Clinical Investigation 121 (2): 671–682.
Guimarães, M.R., F.R. Leite, L.C. Spolidorio, K.L. Kirkwood, and C. Rossa Jr. 2013. Curcumin abrogates LPS-induced proinflammatory cytokines in RAW 264.7 macrophages. Evidence for novel mechanisms involving SOCS-1, -3 and p38 MAPK. Archives of Oral Biology 58 (10): 1309–1317.
Choi, E.Y., S.H. Choe, J.Y. Hyeon, J.I. Choi, I.S. Choi, and S.J. Kim. 2015. Effect of caffeic acid phenethyl ester on Prevotella intermedia lipopolysaccharide-induced production of proinflammatory mediators in murine macrophages. Journal of Periodontal Research 50 (6): 737–747.
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Zhang, H., Zhao, Z., Pang, X. et al. Genistein Protects Against Ox-LDL-Induced Inflammation Through MicroRNA-155/SOCS1-Mediated Repression of NF-ĸB Signaling Pathway in HUVECs. Inflammation 40, 1450–1459 (2017). https://doi.org/10.1007/s10753-017-0588-3
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DOI: https://doi.org/10.1007/s10753-017-0588-3