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Panax notoginseng saponins inhibits atherosclerotic plaque angiogenesis by down-regulating vascular endothelial growth factor and nicotinamide adenine dinucleotide phosphate oxidase subunit 4 expression

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Abstract

Objective

To investigate the mechanism of Panax notoginseng saponins (PNS), an effective component extracted from Panax notoginseng, on atherosclerotic plaque angiogenesis in atherosclerosis-prone apolipoprotein E-knockout (ApoE-KO) mice fed with high-fat, high-cholesterol diet.

Methods

Twenty ApoE-KO mice were divided into two groups, the model group and the PNS group. Ten normal C57BL/6J mice were used as a control group. PNS (60 mg/kg) was orally administered daily for 12 weeks in the PNS group. The ratio of plaque area to vessel area was examined by histological staining. The tissue sample of aortic root was used to detect the CD34 and vascular endothelial growth factor (VEGF) expression areas by immunohistochemistry. The expression of VEGF and nicotinamide adenine dinucleotide phosphate oxidase subunit 4 (NOX4) were measured by reverse transcription polymerase chain reaction and Western blotting respectively.

Results

After treatment with PNS, the plaque areas were decreased (P<0.05). CD34 expressing areas and VEGF expression areas in plaques were significantly decreased (P<0.05). Meanwhile, VEGF and NOX4 mRNA expression were decreased after treatment with PNS. VEGF and NOX4 protein expression were also decreased by about 72% and 63%, respectively (P<0.01).

Conclusion

PNS, which decreases VEGF and NOX4 expression, could alleviate plaque angiogenesis and attenuate atherosclerosis.

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References

  1. Moulton KS, Heller E, Konerding MA, Flynn E, Palinski W, Folkman J. Angiogenesis inhibitors endostatin or TNP-470 reduce intimal neovascularization and plaque growth in apolipoprotein E-deficient mice. Circulation 1999;99:1726–1732.

    Article  CAS  PubMed  Google Scholar 

  2. Ferrara N, Davis-Smyth T. The biology of vascular endothelial growth factor. Endocr Rev 1997;18:4–25.

    Article  CAS  PubMed  Google Scholar 

  3. Celletti FL, Waugh JM, Amabile PG, Brendolan A, Hilfiker PR, Dake MD. Vascular endothelial growth factor enhances atherosclerotic plaque progression. Nat Med 2001;7:425–429.

    Article  CAS  PubMed  Google Scholar 

  4. Ushio-Fukai M, Alexander RW. Reactive oxygen species as mediators of angiogenesis signaling: role of NAD(P)H oxidase. Mol Cell Biochem 2004;264:85–97.

    Article  CAS  PubMed  Google Scholar 

  5. Abid MR, Kachra Z, Spokes KC, Aird WC. NADPH oxidase activity is required for endothelial cell proliferation and migration. FEBS Lett 2000;486:252–256.

    Article  CAS  PubMed  Google Scholar 

  6. Sorescu D, Weiss D, Lassegue B, Clempus RE, Szocs K, Sorescu GP, et al. Superoxide production and expression of nox family proteins in human atherosclerosis. Circulation 2002;105:1429–1435.

    Article  CAS  PubMed  Google Scholar 

  7. Datla SR, Peshavariya H, Dusting GJ, Mahadev K, Goldstein BJ, Jiang F. Important role of NOX4 type NADPH oxidase in angiogenic responses in human microvascular endothelial cells in vitro. Arterioscler Thromb Vasc Biol 2007;27:2319–2324.

    Article  CAS  PubMed  Google Scholar 

  8. Folkman J. Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med 1995;1:27–31.

    Article  CAS  PubMed  Google Scholar 

  9. Moulton KS, Vakili K, Zurakowski D. Inhibition of plaque neovascularization reduces macrophage accumulation and progression of advanced atherosclerosis. Proc Natl Acad Sci U S A 2003;100:4736–4741.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  10. Moulton KS. Plaque angiogenesis and atherosclerosis. Curr Atheroscler Rep 2001;3:225–233.

    Article  CAS  PubMed  Google Scholar 

  11. Di Stefano R, Felice F, Balbarini A. Angiogenesis as risk factor for plaque vulnerability. Curr Pharm Des 2009;15:1095–1106.

    Article  PubMed  Google Scholar 

  12. Liu Y, Chen KJ. Atherosclerosis, vascular aging and Ttherapeutic strategies. Chin J Integr Med 2012;18:83–87.

    Article  CAS  PubMed  Google Scholar 

  13. Fan JS, Liu DN, Huang G, Xu ZZ, Jia Y, Zhang HG, et al. Panax notoginseng saponins attenuate atherosclerosis via reciprocal regulation of lipid metabolism and inflammation by inducing liver x receptor alpha expression. J Ethnopharmacol 2012;142:732–738.

    Article  CAS  PubMed  Google Scholar 

  14. Tao LL, Lei Y, Wang GL, Zhu LQ, Wang Y. Effect of extracts from Radix Ginseng, Radix Notoginseng and Rhizoma Chuanxiong on delaying aging of vascular smooth muscle cells in aged rats. Chin J Integr Med 2012;18:582–590.

    Article  PubMed  Google Scholar 

  15. Dou L, Lu Y, Shen T, Huang X, Man Y, Wang S, et al. Panax notogingseng saponins suppress RAGE/MAPK signaling and NF-kappaB activation in apolipoprotein-Edeficient atherosclerosis-prone mice. Cell Physiol Biochem 2012;29:875–882.

    Article  CAS  PubMed  Google Scholar 

  16. Liu Y, Zhang HG, Jia Y, Li XH. Panax notoginseng saponins attenuate atherogenesis accelerated by zymosan in rabbits. Biol Pharm Bull 2010;33:1324–1330.

    Article  CAS  PubMed  Google Scholar 

  17. Liu G, Wang B, Zhang J, Jiang H, Liu F. Total Panax notoginsenosides prevent atherosclerosis in apolipoprotein E-knockout mice: Role of downregulation of CD40 and MMP-9 expression. J Ethnopharmacol 2009;126:350–354.

    Article  CAS  PubMed  Google Scholar 

  18. Zhang SH, Reddick RL, Piedrahita JA, Maeda N. Spontaneous hypercholesterolemia and arterial lesions in mice lacking apolipoprotein E. Science 1992;258:468–471.

    Article  CAS  PubMed  Google Scholar 

  19. Nakashima Y, Plump AS, Raines EW, Breslow JL, Ross R. ApoE-deficient mice develop lesions of all phases of atherosclerosis throughout the arterial tree. Arterioscler Thrombosis 1994;14:133–140.

    Article  CAS  Google Scholar 

  20. Teo NB, Shoker BS, Martin L, Sloane JP, Holcombe C. Angiogenesis in pre-invasive cancers. Anticancer Res 2002;22:2061–2072.

    CAS  PubMed  Google Scholar 

  21. Hannen EJ, Riediger D. The quantification of angiogenesis in relation to metastasis in oral cancer: a review. Int J Oral Maxillofac Surg 2004;33:2–7.

    Article  CAS  PubMed  Google Scholar 

  22. Krause DS, Fackler MJ, Civin CI, May WS. CD34: structure, biology, and clinical utility. Blood 1996;87:1–13.

    CAS  PubMed  Google Scholar 

  23. Poncelet C, Madelenat P, Feldmann G, Walker F, Darai E. Expression of vonWillebrand’s factor, CD34, CD31, and vascular endothelial growth factor in uterine leiomyomas. Fertil Steril 2002;78:581–586.

    Article  PubMed  Google Scholar 

  24. Matsumoto T, Claesson-Welsh L. VEGF receptor signal transduction. Sci STKE 2001;2001:RE21.

    CAS  PubMed  Google Scholar 

  25. Herrmann J, Lerman LO, Mukhopadhyay D, Napoli C, Lerman A. Angiogenesis in atherogenesis. Arterioscler Thromb Vasc Biol 2006;26:1948–1957.

    Article  CAS  PubMed  Google Scholar 

  26. Celletti FL, Hilfiker PR, Ghafouri P, Dake MD. Effect of human recombinant vascular endothelial growth factor165 on progression of atherosclerotic plaque. J Am Coll Cardiol 2001;37:2126–2130.

    Article  CAS  PubMed  Google Scholar 

  27. Ushio-Fukai M. Redox signaling in angiogenesis: role of NADPH oxidase. Cardiovasc Res 2006;71:226–235.

    Article  CAS  PubMed  Google Scholar 

  28. Nespereira B, Perez-Ilzarbe M, Fernandez P, Fuentes AM, Paramo JA, Rodriguez JA. Vitamins C and E downregulate vascular VEGF and VEGFR-2 expression in apolipoprotein-E-deficient mice. Atherosclerosis 2003;171:67–73.

    Article  CAS  PubMed  Google Scholar 

  29. Ushio-Fukai M, Urao N. Novel role of NADPH oxidase in angiogenesis and stem/progenitor cell function. Antioxid Redox Signal 2009;11:2517–2533.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  30. Chen JX, Zeng H, Lawrence ML, Blackwell TS, Meyrick B. Angiopoietin-1-induced angiogenesis is modulated by endothelial NADPH oxidase. Am J Physiol Heart Circ Physiol 2006;291:H1563–H1572.

    Article  CAS  PubMed  Google Scholar 

  31. Ago T, Kitazono T, Ooboshi H, Iyama T, Han YH, Takada J, et al. NOX4 as the major catalytic component of an endothelial NAD(P)H oxidase. Circulation 2004;109:227–233.

    Article  CAS  PubMed  Google Scholar 

  32. Meng D, Mei A, Liu J, Kang X, Shi X, Qian R, et al. NADPH oxidase 4 mediates insulin-stimulated HIF-1α and VEGF expression, and angiogenesis in vitro. PLoS One 2012;7:e48393.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  33. Zheng H, Liu C, Ou Y, Zhang Y, Fu X. Total saponins of Panax notoginseng enhance VEGF and relative receptors signals and promote angiogenesis derived from rat bone marrow mesenchymal stem cells. J Ethnopharmacol 2013;147:595–602.

    Article  CAS  PubMed  Google Scholar 

  34. Hong SJ, Wan JB, Zhang Y, Hu G, Lin HC, Seto SW, et al. Angiogenic effect of saponin extract from Panax notoginseng on HUVECs in vitro and zebrafish in vivo. Phytother Res 2009;23:677–686.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Traditional Chinese Medicine, Qilu Hospital, Shandong University, Jinan, 250012, China

    Yun Qiao  (乔 云), Min Ren  (任 敏), Lei Yan  (闫 磊) & Ji-dong Zhang  (张继东)

  2. Institution of Biochemistry and Molecular Biology, Medical School of Shandong University, Jinan, 250012, China

    Peng-ju Zhang  (张鹏举)

  3. Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital, Shandong University, Jinan, 250012, China

    Xiao-ting Lu  (鹿晓婷)

  4. Basic Medical College of Shandong University of Traditional Chinese Medicine, Jinan, 250355, China

    Wei-wei Sun  (孙巍巍)

  5. Second Hospital, Shandong University of Traditional Chinese Medicine, Jinan, 250001, China

    Gui-lin Liu  (刘桂林)

Authors
  1. Yun Qiao  (乔 云)
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  2. Peng-ju Zhang  (张鹏举)
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  3. Xiao-ting Lu  (鹿晓婷)
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  4. Wei-wei Sun  (孙巍巍)
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  5. Gui-lin Liu  (刘桂林)
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  6. Min Ren  (任 敏)
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  7. Lei Yan  (闫 磊)
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  8. Ji-dong Zhang  (张继东)
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Correspondence to Ji-dong Zhang  (张继东).

Additional information

Supported by the Plans for the Development of Traditional Chinese Medicine Science and Technology of Shandong Province (No. 2011-203)

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Qiao, Y., Zhang, Pj., Lu, Xt. et al. Panax notoginseng saponins inhibits atherosclerotic plaque angiogenesis by down-regulating vascular endothelial growth factor and nicotinamide adenine dinucleotide phosphate oxidase subunit 4 expression. Chin. J. Integr. Med. 21, 259–265 (2015). https://doi.org/10.1007/s11655-014-1832-4

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  • DOI: https://doi.org/10.1007/s11655-014-1832-4

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