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Inhibitory Effect of Delphinidin on Monocyte–Endothelial Cell Adhesion Induced by Oxidized Low-Density Lipoprotein via ROS/p38MAPK/NF-κB Pathway

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Abstract

Monocyte adhesion to the vascular endothelium and their subsequent trans-endothelial migration are pivotal early events in atherogenesis. In this study, the effect of delphinidin, belonging to the group of anthocyanin, on adhesion of monocytes to endothelial cells induced by ox-LDL was investigated. The results showed that the pre-treatment with delphinidin (50, 100, or 200 μM) dose-dependently decreased the ox-LDL-induced up-regulation of the expression of ICAM-1 and P-selectin, and the enhanced adhesion and transmigration of monocytes. To determine the role of ROS/p38MAPK/NF-κB pathway, intracellular ROS level, p38MAPK protein expression, NF-κB transcription activity and protein expression, IκB-α degradation, NADPH oxidase subunit (Nox2 and p22phox) protein, and mRNA expression were measured. The results showed that delphinidin attenuated ox-LDL-induced generation of ROS, p38MAPK protein expression, NF-κB transcription activity and protein expression, IκB-α degradation, NADPH oxidase subunit (Nox2 and p22phox) protein and mRNA expression in endothelial cells in a dose-dependent manner. These results suggest that delphinidin attenuates ox-LDL induced expression of adhesion molecules (P-selectin and ICAM-1) and the adhesion of monocytes to endothelial cells by inhibiting ROS/p38MAPK/NF-κB pathway. These findings provide a basis for the design of potent antiatherosclerotic agents that will have therapeutic potential in the prevention of AS.

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Abbreviations

ox-LDL:

Oxidized low density lipoprotein

NADPH:

Nicotinamide adenine dinucleotide phosphate

ROS:

Reactive oxygen species

NF-κB:

Nuclear factor-κB

MCP-1:

Monocyte chemoattractant protein-1

LOX-1:

Lectin-like low density lipoprotein-1

ICAM-1:

Intercellular adhesion molecule-1

VCAM-1:

Vascular cell adhesion molecule-1

sICAM-1:

Soluble intercellular adhesion molecule-1

AS:

Atherosclerosis

References

  1. Ross, R. (1999). Atherosclerosis—an inflammatory disease. New England Journal of Medicine, 340, 115–126.

    Article  CAS  PubMed  Google Scholar 

  2. Price, D. T., & Loscalzo, J. (1999). Cellular adhesion molecules and atherogenesis. American Journal of Medicine, 107, 85–97.

    Article  CAS  PubMed  Google Scholar 

  3. Joris, I., Zand, T., Nunnari, J. J., Krolikowski, F. J., & Majno, G. (1983). Studies on the pathogenesis of atherosclerosis: I. Adhesion and emigration of mononuclear cells in the aorta of hypercholesterolemic rats. American Journal of Pathology, 113, 341–358.

    CAS  PubMed  Google Scholar 

  4. Blankenberg, S., Barbaux, S., & Tiret, L. (2003). Adhesion molecules and atherosclerosis. Atherosclerosis, 170, 191–203.

    Article  CAS  PubMed  Google Scholar 

  5. Davì, G., Romano, M., Mezzetti, A., Procopio, A., Iacobelli, S., Antidormi, T., et al. (1998). Increased levels of soluble P-selectin in hypercholesterolemic patients. Circulation, 97, 953–957.

    PubMed  Google Scholar 

  6. Parissis, J. T., Venetsanou, K. F., Mentzikof, D. G., Kalantzi, M. V., Georgopoulou, M. V., & Chrisopoulos, N. (2001). Plasma levels of soluble cellular adhesion molecules in patients with arterial hypertension. The European Journal of Internal Medicine, 12, 350–356.

    Article  Google Scholar 

  7. Cernuda-Morollón, E., & Ridley, A. J. (2006). Rho GTPases and leukocyte adhesion receptor expression and function in endothelial cells. Circulation Research, 98, 757–767.

    Article  PubMed  Google Scholar 

  8. Witztum, J. L., & Steinberg, D. (1991). Role of oxidized low-density lipoprotein in atherogenesis. Journal of Clinical Investigation, 88, 1785–1792.

    Article  CAS  PubMed  Google Scholar 

  9. Kita, T., Kume, N., Ishii, K., Horiuchi, H., Arai, H., & Yokode, M. (1999). Oxidized LDL and expression of monocyte adhesion molecules. Diabetes Research and Clinical Practice, 45, 1126–1223.

    Article  Google Scholar 

  10. Hirata, K., Miki, N., Kuroda, Y., Sakoda, T., Kawashima, S., & Yokoyama, M. (1995). Low concentration of oxidized low-density lipoprotein and lysophosphatidylcholine upregulate constitutive nitric oxide synthase mRNA expression in bovine aortic endothelial cells. Circulation Research, 76, 958–962.

    CAS  PubMed  Google Scholar 

  11. Francone, O. L., Tu, M., Royer, L. J., Zhu, J., Stevens, K., Oleynek, J. J., et al. (2009). The hydrophobic tunnel present in LOX-1 is essential for oxidized LDL recognition and binding. Journal of Lipid Research, 50, 546–555.

    Article  CAS  PubMed  Google Scholar 

  12. Cominacini, L., Pasini, A. F., Garbin, U., Davoli, A., Tosetti, M. L., Campagnola, M., et al. (2000). Oxidized low-density lipoprotein binding to LOX-1 in endothelial cells induces the activation of NF-κB through an increased production of intracellular reactive oxygen species. Journal of Biological Chemistry, 275, 12633–12638.

    Article  CAS  PubMed  Google Scholar 

  13. Honjo, M., Nakamura, K., Yamashiro, K., Kiryu, J., Tanihara, H., McEvoy, L. M., et al. (2003). Lectin-like oxidised LDL receptor-1 is a cell-adhesion molecule involved in endotoxin-induced inflammation. Proceedings of the National Academy of Sciences of the United States of America, 100, 1274–1279.

    Article  CAS  PubMed  Google Scholar 

  14. Dje N’Guessan, P., Riediger, F., Vardarova, K., Scharf, S., Eitel, J., Opitz, B., et al. (2009). Statins control oxidized LDL-mediated histone modifications and gene expression in cultured human endothelial cells. Arteriosclerosis, Thrombosis, and Vascular Biology, 29, 380–386.

    Article  PubMed  Google Scholar 

  15. Lazzè, M. C., Pizzala, R., Perucca, P., Cazzalini, O., Savio, M., Forti, L., et al. (2006). Anthocyanidins decrease endothelin-1 production and increase endothelial nitric oxide synthase in human endothelial cells. Molecular Nutrition & Food Research, 50, 44–51.

    Article  Google Scholar 

  16. Yi, L., Chen, C. Y., Jin, X., Mi, M. T., Yu, B., Chang, H., et al. (2010). Structural requirements of anthocyanins in relation to inhibition of endothelial injury induced by oxidized low-density lipoprotein and correlation with radical scavenging activity. FEBS Letters, 584, 583–590.

    Article  CAS  PubMed  Google Scholar 

  17. Chen, C. Y., Yi, L., Jin, X., Mi, M. T., Zhang, T., Ling, W. H., et al. (2010). Delphinidin attenuates stress injury induced by oxidized low-density lipoprotein in human umbilical vein endothelial cells. Chemico-Biological Interactions, 183, 105–112.

    Article  CAS  PubMed  Google Scholar 

  18. Ushio-Fukai, M. (2006). Redox signaling in angiogenesis: role of NADPH oxidase. Cardiovascular Research, 71, 226–235.

    Article  CAS  PubMed  Google Scholar 

  19. Sternberg, D. (1997). Low density lipoprotein oxidation and its pathobiological significance. Journal of Biological Chemistry, 272, 20963–20966.

    Article  Google Scholar 

  20. Jiang, J. L., Zhu, H. Q., Chen, Z., Xu, H. Y., & Li, Y. J. (2005). Angiotensinconverting enzyme inhibitors prevent LDL-induced endothelial dysfunction by reduction of asymmetric dimethylarginine level. International Journal of Cardiology, 101, 153–155.

    Article  PubMed  Google Scholar 

  21. Hou, G., Xue, L., Lu, Z., Fan, T., Tian, F., & Xue, Y. (2007). An activated mTOR/p70S6 K signaling pathway in esophageal squamous cell carcinoma cell lines and inhibition of the pathway by rapamycin and siRNA against mTOR. Cancer Letters, 253, 236–248.

    Article  CAS  PubMed  Google Scholar 

  22. Korge, P., Ping, P., & Weiss, J. N. (2008). Reactive oxygen species production in energized cardiac mitochondria during hypoxia/reoxygenation: modulation by nitric oxide. Circulation Research, 103, 873–880.

    Article  CAS  PubMed  Google Scholar 

  23. Dou, J. L., Tan, C. Y., Du, Y. G., Bai, X. F., Wang, K. Y., & Ma, X. J. (2007). Effects of chitooligosaccharides on rabbit neutrophils in vitro. Carbohydrate Polymers, 69, 209–213.

    Article  CAS  Google Scholar 

  24. Mendis, E., Kim, M. M., Rajapakse, N., & Kim, S. K. (2007). An in vitro cellular analysis of the radical scavenging efficacy of chitooligosaccharides. Life Science, 80, 2118–2127.

    Article  CAS  Google Scholar 

  25. Jiang, J. L., Wang, S., Li, N. S., Zhang, X. H., Deng, H. W., & Li, Y. J. (2007). The inhibitory effect of simvastatin on the ADMA-induced inflammatory reaction is mediated by MAPK pathways in endothelial cells. Biochemistry and Cell Biology, 85, 66–77.

    Article  CAS  PubMed  Google Scholar 

  26. Zhang, G. G., Bai, Y. P., Chen, M. F., Shi, R. Z., Jiang, D. J., Fu, Q. M., et al. (2008). Asymmetric dimethylarginine induces TNF-alpha production via ROS/NF-kappaB dependent pathway in human monocytic cells and the inhibitory effect of reinioside C. Vascular Pharmacology, 48, 115–121.

    Article  PubMed  Google Scholar 

  27. Mehta, J. L., Chen, J., Hermonat, P. L., Romeo, F., & Novelli, G. (2006). Lectin-like, oxidized low-density lipoprotein receptor-1 (LOX-1): a critical player in the development of atherosclerosis and related disorders. Cardiovascular Research, 69, 36–45.

    Article  CAS  PubMed  Google Scholar 

  28. Cybulsky, M. A., & Gimbrone, M. A. (1991). Endothelial expression of a mononuclear leukocyte adhesion molecule during atherogenesis. Science, 251, 788–791.

    Article  CAS  PubMed  Google Scholar 

  29. Takei, A., Huang, Y., & Lopes-Virella, M. F. (2001). Expression of adhesion molecules by human endothelial cells exposed to oxidized low density lipoprotein. Influences of degree of oxidation and location of oxidized LDL. Atherosclerosis, 154, 79–86.

    Article  CAS  PubMed  Google Scholar 

  30. Huo, Y., Weber, C., Forlow, S. B., Sperandio, M., Thatte, J., Mack, M., et al. (2001). The chemokine KC, but not monocyte chemoattractant protein-1, triggers monocyte arrest on early atherosclerotic endothelium. Journal of Clinical Investigation, 108, 1307–1314.

    CAS  PubMed  Google Scholar 

  31. Luscinskas, F. W., Kansas, G. S., Ding, H., Pizcueta, P., Schleiffenbaum, B. E., Tedder, T. F., et al. (1994). Monocyte rolling, arrest and spreading on IL-4–activated vascular endothelium under flow is mediated via sequential action of l-selectin, beta 1-integrins, and beta 2-integrins. Journal of Cell Biology, 125, 1417–1427.

    Article  CAS  PubMed  Google Scholar 

  32. Andrea, K., & Hubbard, R. R. (2000). Intercellular adhesion molecule-1 (ICAM-1) expression and cell signaling cascades. Free Radical Biology and Medicine, 28, 1379–1386.

    Article  Google Scholar 

  33. Subramaniam, M., Saffaripour, S., Watson, S. R., Mayadas, T. N., Hynes, R. O., & Wagner, D. D. (1995). Reduced recruitment of inflammatory cells in a contact hypersensitivity response in P-selectin-deficient mice. Journal of Experimental Medicine, 181, 2277–2282.

    Article  CAS  PubMed  Google Scholar 

  34. Collins, R. G., Velji, R., Guevara, N. V., Hicks, M. J., Chan, L., & Beaudet, A. L. (2000). P-selectin or intercellular adhesion molecule (ICAM)-1 deficiency substantially protects against atherosclerosis in apolipoprotein E-deficient mice. Journal of Experimental Medicine, 191, 189–194.

    Article  CAS  PubMed  Google Scholar 

  35. Dong, Z. M., Brown, A. A., & Wagner, D. D. (2000). Prominent role of P-selectin in the development of advanced atherosclerosis in apoE-deficient mice. Circulation, 101, 2290–2295.

    CAS  PubMed  Google Scholar 

  36. Grumbach, I. M., Chen, W., Mertens, S. A., & Harrison, D. G. (2005). A negative feedback mechanism involving nitric oxide and nuclear factor kappa-B modulates endothelial nitric oxide synthase transcription. Journal of Molecular and Cellular Cardiology, 39, 595–603.

    Article  CAS  PubMed  Google Scholar 

  37. Mitchell, D. A., Morton, S. U., Fernhoff, N. B., & Marletta, M. A. (2007). Thioredoxin is required for S-nitrosation of procaspase-3 and the inhibition of apoptosis in Jurkat cells. Proceedings of the National Academy of Sciences of the United States of America, 104, 11609–11614.

    Article  CAS  PubMed  Google Scholar 

  38. Ckless, K., van der Vliet, A., & Janssen-Heininger, Y. (2007). Oxidative-nitrosative stress and post-translational protein modifications: implications to lung structure-function relations. Arginase modulates NF-kappaB activity via a nitric oxide-dependent mechanism. American Journal of Respiratory Cell and Molecular Biology, 36, 645–653.

    Article  CAS  PubMed  Google Scholar 

  39. Takano, M., Meneshian, A., Sheikh, E., Yamakawa, Y., Wilkins, K. B., Hopkins, E. A., et al. (2002). Rapid upregulation of endothelial P-selectin expression via reactive oxygen species generation. American Journal of Physiology-Heart and Circulatory Physiology, 5, 2054–2061.

    Google Scholar 

  40. Lum, H., & Roebuck, K. A. (2001). Oxidant stress and endothelial dysfunction. American Journal of Physiology-Cell Physiology, 280, 719–741.

    Google Scholar 

  41. de Winther, M. P., Kanters, E., & Kraal, G. (2005). Nuclear factor κB signaling in atherogenesis. Arteriosclerosis, Thrombosis, and Vascular Biology, 25, 904–914.

    Article  CAS  PubMed  Google Scholar 

  42. Burleigh, M. E., Babaev, V. R., Yancey, P. G., Major, A. S., McCaleb, J. L., Oates, J. A., et al. (2005). Cyclooxygenase-2 promotes early atherosclerotic lesion formation in ApoE-deficient and C57BL/6 mice. Journal of Molecular and Cellular Cardiology, 39, 443–452.

    Article  CAS  PubMed  Google Scholar 

  43. Gu, L., Okada, Y., Clinton, S. K., Gerard, C., Sukhova, G. K., Libby, P., et al. (1998). Absence of monocyte chemoattractant protein-1 reduces atherosclerosis in low density lipoprotein receptor-deficient mice. Molecular Cell, 2, 275–281.

    Article  CAS  PubMed  Google Scholar 

  44. Niemann-Jonsson, A., Dimayuga, P., & Jovinge, S. (2000). Accumulation of LDL in rat arteries is associated with activation of tumor necrosis factor-alpha expression. Arteriosclerosis, Thrombosis, and Vascular Biology, 20, 2205–2211.

    Article  CAS  PubMed  Google Scholar 

  45. Janssen-Heininger, Y. M. W., Poynter, M. E., & Baeuerle, P. A. (2000). Recent advances towards understanding redox mechanisms in the activation of nuclear factor κB. Free Radical Biology and Medicine, 28, 1317–1327.

    Article  CAS  PubMed  Google Scholar 

  46. Bar-Shai, M., Carmeli, E., Ljubuncic, P., & Reznick, A. Z. (2008). Exercise and immobilization in aging animals: the involvement of oxidative stress and NF-kappaB activation. Free Radical Biology and Medicine, 44, 202–214.

    Article  CAS  PubMed  Google Scholar 

  47. Elks, C. M., Mariappan, N., Haque, M., Guggilam, A., Majid, D. S., & Francis, J. (2009). Chronic NF-κB blockade reduces cytosolic and mitochondrial oxidative stress and attenuates renal injury and hypertension in SHR. American Journal of Physiology-Renal Physiology, 296, 298–305.

    Article  Google Scholar 

  48. Mazza, G. J. (2007). Anthocyanins and heart health. Annals of the 1st Super Sanita, 43, 369–374.

    CAS  Google Scholar 

  49. Xu, J. W., Ikeda, K., & Yamori, Y. (2004). Upregulation of endothelial nitricoxide synthase by cyanidin-3-glucoside, a typical anthocyanin pigment. Hypertension, 44, 217–222.

    Article  CAS  PubMed  Google Scholar 

  50. Mertens-Talcott, S. U., Rios, J., Jilma-Stohlawetz, P., Pacheco-Palencia, L. A., Meibohm, B., Talcott, S. T., et al. (2008). Pharmacokinetics of anthocyanins and antioxidant effects after the consumption of anthocyanin-rich acai juice and pulp (Euterpe oleracea Mart.) in human healthy volunteers. Journal of Agriculture and Food Chemistry, 56, 7796–7802.

    Article  CAS  Google Scholar 

  51. Song, J., Li, Y., Ge, J., Duan, Y., Sze, S. C., Tong, Y., et al. (2010). Protective effect of bilberry (Vaccinium myrtillus L.) extracts on cultured human corneal limbal epithelial cells (HCLEC). Phytotherapy Research, 24, 520–524.

    CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported by National Natural Science Foundation of China (grant number 81000133), “the 11th Five-year Plan” for National Key Technology Research and Development Program (2008BAI58B06), and the Innovation Project of Chongqing Key Laboratory of Nutrition and Food Safety (2006CA1003).

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Authors and Affiliations

  1. Research Center of Nutrition and Food Safety, Chongqing Key Laboratory of Nutrition and Food Safety, The Third Military Medical University, Chongqing, 400038, People’s Republic of China

    Chun-ye Chen, Long Yi, Xin Jin, Ting Zhang, Yu-jie Fu, Jun-dong Zhu, Man-tian Mi, Qian-yong Zhang & Bin Yu

  2. Department of Medical Nutriology, School of Public Health, Sun Yat-Sen University, Guangzhou, 510080, People’s Republic of China

    Wen-hua Ling

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  1. Chun-ye Chen
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  2. Long Yi
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Correspondence to Man-tian Mi or Qian-yong Zhang.

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Chun-ye Chen and Long Yi contributed equally to this work.

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Chen, Cy., Yi, L., Jin, X. et al. Inhibitory Effect of Delphinidin on Monocyte–Endothelial Cell Adhesion Induced by Oxidized Low-Density Lipoprotein via ROS/p38MAPK/NF-κB Pathway. Cell Biochem Biophys 61, 337–348 (2011). https://doi.org/10.1007/s12013-011-9216-2

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