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6-Gingerol Ameliorates Behavioral Changes and Atherosclerotic Lesions in ApoE−/− Mice Exposed to Chronic Mild Stress

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Abstract

Chronic mild stress (CMS) has been demonstrated to contribute to atherosclerosis. 6-gingerol (6-Gin), a phenolic component of ginger (Zingiber officinale), has been shown to exert numerous pharmacological properties, such as anti-inflammatory and cardioprotective effects. Here we investigated the role of CMS in the development of atherosclerosis in high-fat diet (HFD)-fed ApoE−/− mice and evaluated the potential therapeutic effects of 6-Gin. Mice were exposed to CMS for 20 weeks, at week 5, they were fed with a high-fat diet (HFD), then received 6-Gin (20 mg/kg/day, intragastrically) treatment. Antiatherosclerotic simvastatin (Sim) and antidepressant lorazepam (Lor) were used for positive drugs. The behavioral and atherosclerotic changes, plasma lipid profiles as well as inflammatory cytokine levels were measured. Our results showed that CMS-exposed mice exhibited reduced body weight gain, sucrose preference and locomotor activity, which are representative of some of the core symptoms of depression. Furthermore, CMS challenge aggravated atherosclerotic lesions, as indicated by increased plaque formation, elevation of plasma total cholesterol, triglyceride, low-density lipoprotein cholesterin, and proinflammatory cytokines including TNF-α, IL-1β, and IL-6. In addition, the expression levels of phosphorylated adenosine monophosphate-activated protein kinase (p-AMPK), acetyl-CoA carboxylase (ACC), hHMG-CoA reductase (HMGCR), fatty acid synthase (FAS), sterol regulatory element binding protein (SREBP)-1 and SREBP-2 in the liver tissues were altered after CMS exposure. 6-Gin not only improved the behavioral changes, but also alleviated atherosclerotic lesions, and reversed the expression levels of lipid profiles and inflammatory cytokines in stressed mice. Moreover, the antiatherosclerotic effects of 6-Gin is mediated in part by the AMPK signaling pathway, which is closely associated with cholesterol synthesis and lipid accumulation. Together, these results suggest that 6-Gin attenuates arteriosclerosis in ApoE−/− mice exposed to CMS and HFD, and it may be a potential therapeutic agent for the treatment of atherosclerosis.

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References

  1. Manduteanu, I., & Simionescu, M. (2012). Inflammation in atherosclerosis: A cause or a result of vascular disorders? Journal of Cellular and Molecular Medicine, 16(9), 1978–1990. https://doi.org/10.1111/j.1582-4934.2012.01552.x.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  2. Libby, P. (2002). Inflammation in atherosclerosis. Nature, 420(6917), 868–874. https://doi.org/10.1038/nature01323.

    Article  PubMed  CAS  Google Scholar 

  3. Lusis, A. J. (2000). Atherosclerosis. Nature, 407(6801), 233–241. https://doi.org/10.1038/35025203.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. Hansson, G. K. (2005). Inflammation, atherosclerosis, and coronary artery disease. The New England Journal of Medicine, 352(16), 1685–1695. https://doi.org/10.1056/NEJMra043430.

    Article  PubMed  CAS  Google Scholar 

  5. Fruchart, J. C., Nierman, M. C., Stroes, E. S., Kastelein, J. J., & Duriez, P. (2004). New risk factors for atherosclerosis and patient risk assessment. Circulation, 109(23), 15–19. https://doi.org/10.1161/01.cir.0000131513.33892.5b.

    Article  Google Scholar 

  6. Steptoe, A., & Kivimaki, M. (2012). Stress and cardiovascular disease. Nature Reviews Cardiology, 9(6), 360–370. https://doi.org/10.1038/nrcardio.2012.45.

    Article  PubMed  CAS  Google Scholar 

  7. Ranjit, N., Diez-Roux, A. V., Shea, S., Cushman, M., Seeman, T., Jackson, S. A., et al. (2007). Psychosocial factors and inflammation in the multi-ethnic study of atherosclerosis. Archives of Internal Medicine, 167(2), 174–181. https://doi.org/10.1001/archinte.167.2.174.

    Article  PubMed  Google Scholar 

  8. Wang, S., Xiaoling, G., Pingting, L., Shuqiang, L., & Yuaner, Z. (2014). Chronic unpredictable mild stress combined with a high-fat diets aggravates atherosclerosis in rats. Lipids in Health and Disease, 13, 77. https://doi.org/10.1186/1476-511X-13-77.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Gu, H., Tang, C., Peng, K., Sun, H., & Yang, Y. (2009). Effects of chronic mild stress on the development of atherosclerosis and expression of toll-like receptor 4 signaling pathway in adolescent apolipoprotein E knockout mice. Journal of Biomedicine and Biotechnology, 2009, 613879. https://doi.org/10.1155/2009/613879.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Kumari, M., Grahame-Clarke, C., Shanks, N., Marmot, M., Lightman, S., & Vallance, P. (2003). Chronic stress accelerates atherosclerosis in the apolipoprotein E deficient mouse. Stress, 6(4), 297–299. https://doi.org/10.1080/10253890310001619461.

    Article  PubMed  CAS  Google Scholar 

  11. Sultan, M. T. (2011). Ginger and its health claims: molecular aspects. Critical Reviews in Food Science and Nutrition, 51(5), 383.

    Article  PubMed  CAS  Google Scholar 

  12. Kubra, I. R., & Rao, L. J. (2012). An impression on current developments in the technology, chemistry, and biological activities of ginger (Zingiber officinale Roscoe). Critical Reviews in Food Science and Nutrition, 52(8), 651.

    Article  PubMed  CAS  Google Scholar 

  13. Ho, S. C., Chang, K. S., & Lin, C. C. (2013). Anti-neuroinflammatory capacity of fresh ginger is attributed mainly to 10-gingerol. Food Chemistry, 141(3), 3183–3191. https://doi.org/10.1016/j.foodchem.2013.06.010.

    Article  PubMed  CAS  Google Scholar 

  14. Ajayi, B. O., Adedara, I. A., & Farombi, E. O. (2015). Pharmacological activity of 6-gingerol in dextran sulphate sodium-induced ulcerative colitis in BALB/c mice. Phytotherapy Research: PTR, 29(4), 566–572. https://doi.org/10.1002/ptr.5286.

    Article  PubMed  CAS  Google Scholar 

  15. Gundala, S. R., Mukkavilli, R., Yang, C., Yadav, P., Tandon, V., Vangala, S., et al. (2014). Enterohepatic recirculation of bioactive ginger phytochemicals is associated with enhanced tumor growth-inhibitory activity of ginger extract. Carcinogenesis, 35(6), 1320–1329. https://doi.org/10.1093/carcin/bgu011.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Srinivasan, K. (2014). Antioxidant potential of spices and their active constituents. Critical Reviews in Food Science and Nutrition, 54(3), 352–372. https://doi.org/10.1080/10408398.2011.585525.

    Article  PubMed  CAS  Google Scholar 

  17. Liu, Q., Liu, J., Guo, H., Sun, S., Wang, S., Zhang, Y., et al. (2013). 6-gingerol: A novel AT(1) antagonist for the treatment of cardiovascular disease. Planta Medica, 79(5), 322–326. https://doi.org/10.1055/s-0032-1328262.

    Article  PubMed  CAS  Google Scholar 

  18. El-Bassossy, H. M., Elberry, A. A., Ghareib, S. A., Azhar, A., Banjar, Z. M., & Watson, M. L. (2016). Cardioprotection by 6-gingerol in diabetic rats. Biochemical and Biophysical Research Communications, 477(4), 908–914. https://doi.org/10.1016/j.bbrc.2016.06.157.

    Article  PubMed  CAS  Google Scholar 

  19. Ghareib, S. A., El-Bassossy, H. M., Elberry, A. A., Azhar, A., Watson, M. L., & Banjar, Z. M. (2015). 6-Gingerol alleviates exaggerated vasoconstriction in diabetic rat aorta through direct vasodilation and nitric oxide generation. Drug Design, Development and Therapy, 9, 6019–6026. https://doi.org/10.2147/DDDT.S94346.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Okamoto, M., Irii, H., Tahara, Y., Ishii, H., Hirao, A., Udagawa, H., et al. (2011). Synthesis of a new [6]-gingerol analogue and its protective effect with respect to the development of metabolic syndrome in mice fed a high-fat diet. Journal of Medicinal Chemistry, 54(18), 6295–6304. https://doi.org/10.1021/jm200662c.

    Article  PubMed  CAS  Google Scholar 

  21. Tang, Y. L., Jiang, J. H., Wang, S., Liu, Z., Tang, X. Q., Peng, J., et al. (2015). TLR4/NF-kappaB signaling contributes to chronic unpredictable mild stress-induced atherosclerosis in ApoE−/− mice. PLoS ONE, 10(4), e0123685. https://doi.org/10.1371/journal.pone.0123685.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Yalcin, I., Aksu, F., & Belzung, C. (2005). Effects of desipramine and tramadol in a chronic mild stress model in mice are altered by yohimbine but not by pindolol. European Journal of Pharmacology, 514(2–3), 165–174. https://doi.org/10.1016/j.ejphar.2005.03.029.

    Article  PubMed  CAS  Google Scholar 

  23. Ismail, B., Aboul-Fotouh, S., Mansour, A. A., Shehata, H. H., Salman, M. I., Ibrahim, E. A., et al. (2014). Behavioural, metabolic, and endothelial effects of the TNF-alpha suppressor thalidomide on rats subjected to chronic mild stress and fed an atherogenic diet. Canadian Journal of Physiology and Pharmacology, 92(5), 375–385. https://doi.org/10.1139/cjpp-2013-0446.

    Article  PubMed  CAS  Google Scholar 

  24. Jacobi, J., Maas, R., Cardounel, A. J., Arend, M., Pope, A. J., Cordasic, N., et al. (2010). Dimethylarginine dimethylaminohydrolase overexpression ameliorates atherosclerosis in apolipoprotein E-deficient mice by lowering asymmetric dimethylarginine. The American Journal of Pathology, 176(5), 2559–2570. https://doi.org/10.2353/ajpath.2010.090614.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Zhou, L., Zheng, Y., Li, Z., Bao, L., Dou, Y., Tang, Y., et al. (2016). Compound K attenuates the development of atherosclerosis in ApoE(−/−) Mice via LXRalpha activation. International Journal of Molecular Sciences, 17(7), 1054. https://doi.org/10.3390/ijms17071054.

    Article  PubMed Central  CAS  Google Scholar 

  26. Lu, X. T., Liu, Y. F., Zhang, L., Yang, R. X., Liu, X. Q., Yan, F. F., et al. (2012). Unpredictable chronic mild stress promotes atherosclerosis in high cholesterol-fed rabbits. Psychosomatic Medicine, 74(6), 604–611. https://doi.org/10.1097/PSY.0b013e31825d0b71.

    Article  PubMed  CAS  Google Scholar 

  27. Okamoto, M., Irii, H., Yu, T., Ishii, H., Hirao, A., Udagawa, H., et al. (2011). Synthesis of a new [6]-gingerol analogue and its protective effect with respect to the development of metabolic syndrome in mice fed a high-fat diet. Journal of Medicinal Chemistry, 54(18), 6295.

    Article  PubMed  CAS  Google Scholar 

  28. Kumari, M., Grahame-Clarke, C., Shanks, N., Marmot, M., Lightman, S., & Vallance, P. (2003). Chronic stress accelerates atherosclerosis in the apolipoprotein E deficient mouse. Stress—The International Journal on the Biology of Stress, 6(4), 297–299.

    Article  CAS  Google Scholar 

  29. Dimsdale, J. E. (2002). Psychological stress and cardiovascular disease. Journal of the American College of Cardiology, 325(7359), 337–338.

    Google Scholar 

  30. Willner, P. (1997). Validity, reliability and utility of the chronic mild stress model of depression: A 10-year review and evaluation. Psychopharmacology (Berl), 134(4), 319–329.

    Article  CAS  Google Scholar 

  31. Zhang, T., Chen, Y., Liu, H., Zhou, Z., Zhai, Y., & Yang, J. (2010). Chronic unpredictable stress accelerates atherosclerosis through promoting inflammation in apolipoprotein E knockout mice. Thrombosis Research, 126(5), 386.

    Article  PubMed  CAS  Google Scholar 

  32. Mao, Q. Q., Xian, Y. F., Ip, S. P., Tsai, S. H., & Che, C. T. (2010). Long-term treatment with peony glycosides reverses chronic unpredictable mild stress-induced depressive-like behavior via increasing expression of neurotrophins in rat brain. Behavioural Brain Research, 210(2), 171–177. https://doi.org/10.1016/j.bbr.2010.02.026.

    Article  PubMed  CAS  Google Scholar 

  33. Kumar, B., Kuhad, A., & Chopra, K. (2011). Neuropsychopharmacological effect of sesamol in unpredictable chronic mild stress model of depression: Behavioral and biochemical evidences. Psychopharmacology (Berl), 214(4), 819–828. https://doi.org/10.1007/s00213-010-2094-2.

    Article  CAS  Google Scholar 

  34. Thakare, V. N., Patil, R. R., Oswal, R. J., Dhakane, V. D., Aswar, M. K., & Patel, B. M. (2017). Therapeutic potential of silymarin in chronic unpredictable mild stress induced depressive-like behavior in mice. Journal of Psychopharmacology. https://doi.org/10.1177/0269881117742666.

    Article  PubMed  Google Scholar 

  35. Bruder-Nascimento, T., Campos, D. H., Alves, C., Thomaz, S., Cicogna, A. C., & Cordellini, S. (2013). Effects of chronic stress and high-fat diet on metabolic and nutritional parameters in Wistar rats. Arquivos Brasileiros de Endocrinologia e Metabologia, 57(8), 642–649.

    Article  PubMed  Google Scholar 

  36. Kurhe, Y., Radhakrishnan, M., & Gupta, D. (2014). Ondansetron attenuates depression co-morbid with obesity in obese mice subjected to chronic unpredictable mild stress; an approach using behavioral battery tests. Metabolic Brain Disease, 29(3), 701–710. https://doi.org/10.1007/s11011-014-9574-8.

    Article  PubMed  CAS  Google Scholar 

  37. Ren, Y., Wang, J. L., Zhang, X., Wang, H., Ye, Y., Song, L., et al. (2017). Antidepressant-like effects of ginsenoside Rg2 in a chronic mild stress model of depression. Brain Research Bulletin, 134, 211–219. https://doi.org/10.1016/j.brainresbull.2017.08.009.

    Article  PubMed  CAS  Google Scholar 

  38. Wu, T., Zhong, L., Hong, Z., Li, Y., Liu, X., Pan, L., et al. (2015). The effects of Zanthoxylum bungeanum extract on lipid metabolism induced by sterols. Journal of Pharmacological Sciences, 127(3), 251–259. https://doi.org/10.1016/j.jphs.2014.12.002.

    Article  PubMed  CAS  Google Scholar 

  39. Libby, P., Ridker, P. M., & Maseri, A. (2002). Inflammation and atherosclerosis. Circulation, 105(9), 1135–1143.

    Article  PubMed  CAS  Google Scholar 

  40. Akita, K., Isoda, K., Sato-Okabayashi, Y., Kadoguchi, T., Kitamura, K., Ohtomo, F., et al. (2017). An interleukin-6 receptor antibody suppresses atherosclerosis in atherogenic mice. Frontiers in Cardiovascular Medicine, 4, 84. https://doi.org/10.3389/fcvm.2017.00084.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Liu, Y. Z., Wang, Y. X., & Jiang, C. L. (2017). Inflammation: The common pathway of stress-related diseases. Frontiers in Human Neuroscience, 11, 316. https://doi.org/10.3389/fnhum.2017.00316.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Lu, X. T., Liu, Y. F., Zhao, L., Li, W. J., Yang, R. X., Yan, F. F., et al. (2013). Chronic psychological stress induces vascular inflammation in rabbits. Stress, 16(1), 87–98. https://doi.org/10.3109/10253890.2012.676696.

    Article  PubMed  CAS  Google Scholar 

  43. Branen, L., Hovgaard, L., Nitulescu, M., Bengtsson, E., Nilsson, J., & Jovinge, S. (2004). Inhibition of tumor necrosis factor-alpha reduces atherosclerosis in apolipoprotein E knockout mice. Arteriosclerosis, Thrombosis, and Vascular Biology, 24(11), 2137–2142. https://doi.org/10.1161/01.ATV.0000143933.20616.1b.

    Article  PubMed  CAS  Google Scholar 

  44. Li, Y., Xu, B., Xu, M., Chen, D., Xiong, Y., Lian, M., et al. (2017). 6-Gingerol protects intestinal barrier from ischemia/reperfusion-induced damage via inhibition of p38 MAPK to NF-kappaB signalling. Pharmacological Research, 119, 137–148. https://doi.org/10.1016/j.phrs.2017.01.026.

    Article  PubMed  CAS  Google Scholar 

  45. Algandaby, M. M., El-Halawany, A. M., Abdallah, H. M., Alahdal, A. M., Nagy, A. A., Ashour, O. M., et al. (2016). Gingerol protects against experimental liver fibrosis in rats via suppression of pro-inflammatory and profibrogenic mediators. Naunyn-Schmiedeberg’s Archives of Pharmacology, 389(4), 419–428. https://doi.org/10.1007/s00210-016-1210-1.

    Article  PubMed  CAS  Google Scholar 

  46. Nestel, P. J., Whyte, H. M., & Goodman, D. S. (1969). Distribution and turnover of cholesterol in humans. The Journal of Clinical Investigation, 48(6), 982–991. https://doi.org/10.1172/JCI106079.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Jeon, T. I., & Osborne, T. F. (2012). SREBPs: Metabolic integrators in physiology and metabolism. Trends in Endocrinology and Metabolism, 23(2), 65–72.

    Article  PubMed  CAS  Google Scholar 

  48. Ferré, P., & Foufelle, F. (2007). SREBP-1c transcription factor and lipid homeostasis: Clinical perspective. Hormone Research, 68(2), 72–82.

    Article  PubMed  CAS  Google Scholar 

  49. Miyata, S., Inoue, J., Shimizu, M., & Sato, R. (2015). Xanthohumol improves diet-induced obesity and fatty liver by suppressing sterol regulatory element-binding protein (SREBP) activation. The Journal of Biological Chemistry, 290(33), 20565–20579. https://doi.org/10.1074/jbc.M115.656975.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. Cheon, S. Y., Chung, K. S., Lee, K. J., Choi, H. Y., Ham, I. H., Jung, D. H., et al. (2017). HVC1 ameliorates hyperlipidemia and inflammation in LDLR(−/−) mice. BMC Complementary and Alternative Medicine, 17(1), 222. https://doi.org/10.1186/s12906-017-1734-z.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Kahn, B. B., Alquier, T., Carling, D., & Hardie, D. G. (2005). AMP-activated protein kinase: ancient energy gauge provides clues to modern understanding of metabolism. Cell Metabolism, 1(1), 15–25. https://doi.org/10.1016/j.cmet.2004.12.003.

    Article  PubMed  CAS  Google Scholar 

  52. Hardie, D. G. (2003). Minireview: the AMP-activated protein kinase cascade: The key sensor of cellular energy status. Endocrinology, 144(12), 5179–5183. https://doi.org/10.1210/en.2003-0982.

    Article  PubMed  CAS  Google Scholar 

  53. Li, Y., Xu, S., Mihaylova, M. M., Zheng, B., Hou, X., Jiang, B., et al. (2011). AMPK phosphorylates and inhibits SREBP activity to attenuate hepatic steatosis and atherosclerosis in diet-induced insulin-resistant mice. Cell Metabolism, 13(4), 376–388. https://doi.org/10.1016/j.cmet.2011.03.009.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  54. Ejaz, A., Wu, D., Kwan, P., & Meydani, M. (2009). Curcumin inhibits adipogenesis in 3T3-L1 adipocytes and angiogenesis and obesity in C57/BL mice. The Journal of Nutrition, 139(5), 919–925. https://doi.org/10.3945/jn.108.100966.

    Article  PubMed  CAS  Google Scholar 

  55. Zhu, S., Wang, J., Zhang, Y., Li, V., Kong, J., He, J., et al. (2014). Unpredictable chronic mild stress induces anxiety and depression-like behaviors and inactivates AMP-activated protein kinase in mice. Brain Research, 1576, 81–90. https://doi.org/10.1016/j.brainres.2014.06.002.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

This study was supported by a grant from the Second Special Foundation for National Traditional Chinese Medicine Clinical Research Base Construction of State Administration of Traditional Chinese Medicine (No. JDZX2015049).

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Authors and Affiliations

  1. First Department of Cardiology, The Affiliated Hospital of Liaoning University of Traditional Chinese Medicine, 33 Beiling Avenue, Shenyang, 110032, People’s Republic of China

    Shuai Wang, Ronglai Yang, Yating Jing, Wei Chen, Jinliang Wang, Xian Zheng & Fengrong Wang

  2. Department of Medical Affairs, The Affiliated Hospital of Liaoning University of Traditional Chinese Medicine, Shenyang, 110032, People’s Republic of China

    Miao Tian

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  1. Shuai Wang
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Wang, S., Tian, M., Yang, R. et al. 6-Gingerol Ameliorates Behavioral Changes and Atherosclerotic Lesions in ApoE−/− Mice Exposed to Chronic Mild Stress. Cardiovasc Toxicol 18, 420–430 (2018). https://doi.org/10.1007/s12012-018-9452-4

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