Natural Compounds from Danshen Suppress the Activity of Hepatic Stellate Cells

  • Oh, Seong-Hwan (Department of Family Medicine, Korea University, College of Medicine) ;
  • Cho, Kyung-Hwan (Department of Family Medicine, Korea University, College of Medicine) ;
  • Yang, Beom-Seok (Biomedical Research Center, KIST) ;
  • Roh, Yong-Kyun (Department of Family Medicine, Hallym University, College of Medicine)
  • Published : 2006.09.01

Abstract

Danshen is an herbal medication frequently used in oriental medicine to treat liver or kidney malfunction. In the course of our studies, we observed that compounds purified from Danshen exhibit an inhibitory activity against Discoidin Domain Receptor 2 (DDR2) tyrosine kinase. Through this inhibition, these compounds also inhibited the growth of HSC T6 cells and suppressed the expression of alpha-smooth muscle actin and MMP2, as well as collagen synthesis, all of which are increased in activated liver stellate cells. Given that activation of liver stellate cells is the hallmark of liver fibrosis and that DDR2 plays a critical role in this activation, these results suggest that one of the pharmacological activities of Danshen extract that protects the liver is the inhibition of key cell-signaling kinases, such as DDR2, in liver stellate cells.

Keywords

References

  1. Cohen, P., Protein kinases - the major drug targets of the twenty-first century? Nat. Rev. Drug Discov., 1, 309-315 (2002) https://doi.org/10.1038/nrd773
  2. Dan, L. and Friedman, S. L., Liver fibrogenesis and the role of hepatic stellate cells : New insights and prospects for therapy. Journal of gastroenterology and hepatology, 14, 618-633 (1999) https://doi.org/10.1046/j.1440-1746.1999.01928.x
  3. Diegelmann, R. F. and Evans, M. C., Wound healing: an overview of acute, fibrotic and delayed healing. Front Biosci., 9, 283-289 (2004) https://doi.org/10.2741/1184
  4. Fan, Q. W. and Weiss, W. A., Chemical genetic approaches to the development of cancer therapeutics. Curr. Opin. Genet. Dev., 16, 85-91 (2006) https://doi.org/10.1016/j.gde.2005.12.002
  5. Ferri, N., Carragher, N. O., and Raines, E. W., Role of discoidin domain receptors 1 and 2 in human smooth muscle cellmediated collagen remodeling: potential implications in atherosclerosis and lymphangioleiomyomatosis. Am. J. Pathol., 164, 1575-1585 (2004) https://doi.org/10.1016/S0002-9440(10)63716-9
  6. Friedman, S L., Stellate cell activation in alcoholic fibrosis. Alcohol Clin. Exp. Res., 23, 904-910 (1999)
  7. Hou, G., Vogel, W. F., and Bendeck, M. P., Tyrosine kinase activity of discoidin domain receptor 1 is necessary for smooth muscle cell migration and matrix metalloproteinase expression. Circ. Res., 90, 1147-1149 (2002) https://doi.org/10.1161/01.RES.0000022166.74073.F8
  8. Hsu, Y. C., Lin, Y. L., Chiu, Y. T., Shiao, M S., Lee, C. Y., and Huang, Y. T., Antifibrotic effects of Salvia miltiorrhiza on dimethylnitrosamine-intoxicated rats. J. Biomed. Sci., 12, 185-195 (2005) https://doi.org/10.1007/s11373-004-8167-7
  9. Kang, D. G., Oh, H., Sohn, E. J., Hur, T. Y., Lee, K. C., Kim, K. J., Kim, T. Y., and Lee, H S., Lithospermic acid B isolated from Salvia miltiorrhiza ameliorates ischemia/reperfusioninduced renal injury in rats. Life Sci., 75, 1801-1816 (2004) https://doi.org/10.1016/j.lfs.2004.02.034
  10. Katsuda, S. and Kaji T., Atherosclerosis and extracellular matrix. J. Atheroscler. Thromb., 10, 267-74 (2003) https://doi.org/10.5551/jat.10.267
  11. Li, X., Yu, C., Cai, Y., Liu, G., Jia, J., and Wang, Y., Simultaneous determination of six phenolic constituents of danshen in human serum using liquid chromatography/tandem mass spectrometry. J. Chromatography B., 820, 41-47 (2005) https://doi.org/10.1016/j.jchromb.2005.03.005
  12. Ling, S., Dai, A., Guo, Z., Yan, X., and Komesaroff, P. A., Effects of a Chinese herbal preparation on vascular cells in culture: mechanisms of cardiovascular protection. Clin. Exp. Pharmacol. Physiol., 32, 571-578 (2005) https://doi.org/10.1111/j.1440-1681.2005.04232.x
  13. Olaso, E., Ikeda, K., Eng, F. J., Xu, L., Wang, L. H., Lin, H. C., and Friedman, S. L., DDR2 receptor promotes MMP-2- mediated proliferation and invasion by hepatic stellate cells. J. Clin. Invest., 108, 1369-1378 (2001) https://doi.org/10.1172/JCI200112373
  14. Olaso, E., Labrador, J. P., Wang, L., Ikeda, K., Eng, F. J., Klein, R., Lovett, D. H., Lin, H. C., and Friedman, S. L., Discoidin domain receptor 2 regulates fibroblast proliferation and migration through the extracellular matrix in association with transcriptional activation of matrix metalloproteinase-2. J. Biol. Chem., 277, 3606-3613 (2002) https://doi.org/10.1074/jbc.M107571200
  15. Ramón, B. and David, A. B., Liver fibrosis. J. Clin. Invest., 115, 209-218 (2005) https://doi.org/10.1172/JCI24282
  16. Shrivastava, A., Radziejewski, C., Campbell, E., Kovac, L., McGlynn, M., Ryan, T. E., Davis, S., Goldfarb, M. P., Glass, D. J., Lemke, G., and Yancopoulos, G. D., An orphan receptor 14. tyrosine kinase family whose members serve as nonintegrin collagen receptors. Mol. Cell, 1, 25-34 (1997) https://doi.org/10.1016/S1097-2765(00)80004-0
  17. Vogel, W., Gish, G. D., Alves, F., and Pawson, T., The discoidin domain receptor tyrosine kinases are activated by collagen. Mol Cell., 1, 13-23 (1997) https://doi.org/10.1016/S1097-2765(00)80003-9
  18. Vogel, W., Discoidin domain receptors : structural relations and functional implications. FASEB J., Suppl, S77-82 (1999)
  19. Wang, J., Lu, H., Liu, X., Deng, Y., Sun, T., Li, F., Ji, S., Nie, X., and Yao, L., Functional analysis of discoidin domain receptor 2 in synovial fibroblasts in rheumatoid arthritis. J. Autoimmun., 19, 161-168 (2002) https://doi.org/10.1006/jaut.2002.0606
  20. Yang, K., Kim, J. H., Kim, H. J., Park, I. S., Kim, I. Y., and Yang, B. S., Tyrosine 740 phosphorylation of discoidin domain receptor 2 by Src stimulates intramolecular autophosphorylation and Shc signaling complex formation. J. Biol. Chem., 280, 39058-39066 (2005) https://doi.org/10.1074/jbc.M506921200
  21. Zhou, L., Zuo, Z., and Chow, M S., Danshen: an overview of its chemistry, pharmacology, pharmacokinetics, and clinical use. J. Clin. Pharmacol., 45, 1345-1359 (2005) https://doi.org/10.1177/0091270005282630
  22. Zhu, Y. Z., Huang, S. H., Tan, B. K., Sun, J., Whiteman, M., and Zhu, Y. C., Antioxidants in Chinese herbal medicines: a biochemical perspective. Nat. Prod. Rep., 21, 478-489 (2004) https://doi.org/10.1039/b304821g