Berberine Inhibits the Production of Lysophosphatidylcholine-induced Reactive Oxygen Species and the ERK1/2 Pathway in Vascular Smooth Muscle Cells

  • Cho, Bong Jun (Yonsei Research Institute of Aging Science, Yonsei University) ;
  • Im, Eun Kyoung (Yonsei Research Institute of Aging Science, Yonsei University) ;
  • Kwon, Jun Hye (Yonsei Research Institute of Aging Science, Yonsei University) ;
  • Lee, Kyung-Hye (Yonsei Research Institute of Aging Science, Yonsei University) ;
  • Shin, Hye-Jin (Yonsei Research Institute of Aging Science, Yonsei University) ;
  • Oh, Jaewon (Yonsei Research Institute of Aging Science, Yonsei University) ;
  • Kang, Seok-Min (Yonsei Research Institute of Aging Science, Yonsei University) ;
  • Chung, Ji Hyung (Yonsei Research Institute of Aging Science, Yonsei University) ;
  • Jang, Yangsoo (Yonsei Research Institute of Aging Science, Yonsei University)
  • Received : 2005.08.27
  • Accepted : 2005.09.22
  • Published : 2005.12.31

Abstract

Lysophosphatidylcholine (lysoPC) induces vascular smooth muscle cell (VSMC) proliferation and migration, which has been proposed to initiate the intimal thickening in coronary atherosclerotic lesions. Berberine is an alkaloid in Berberis aquifolium and many other plants. Recently, it has been shown to have beneficial effects on the cardiovascular system, such as anti-hyperglycemic and cholesterol-lowering activity. In this study, we investigated its effects on lysoPC-induced VSMC proliferation and migration. Berberine inhibited lysoPC-induced DNA synthesis and cell proliferation in VSMCs, as well as migration of the lysoPC-stimulated VSMCs. It also inhibited the activation of extracellular signal-regulated kinases (ERKs) and reduced transcription factor AP-1 activity and the lysoPC-induced increases in intracellular reactive oxygen species (ROS). These results indicate that the inhibitory effects of berberine on lysoPC-stimulated VSMC proliferation and migration are attributable to inhibition of ROS generation and hence of activation of the ERK1/2 pathway. This suggests that berberine has potential in the prevention of atherosclerosis and restenosis.

Keywords

Acknowledgement

Supported by : Ministry of Health & Welfare

References

  1. Andres, V. and Castro, C. (2003) Antiproliferative strategies for the treatment of vascular proliferative disease. Curr. Vasc. Pharmacol. 1, 85-98 https://doi.org/10.2174/1570161033386763
  2. Chen, K., Thomas, S. R., and Keaney, J. F. Jr. (2003) Beyond LDL oxidation: ROS in vascular signal transduction. Free Radic. Biol. Med. 35, 117-132 https://doi.org/10.1016/S0891-5849(03)00239-9
  3. Cho, H. M., Choi, S. H., Hwang, K. C., Oh, S. Y., Kim, H. G., et al. (2005) The Src/PLC/PKC/MEK/ERK signaling pathway is involved in aortic smooth muscle cell proliferation induced by glycated LDL. Mol. Cells 19, 60-66
  4. Choi, S. H., Cho, S. K., Kang, S. S., Bae, C. S., Bai, Y. H., et al. (2003) Effect of apitherapy in piglets with preweaning diarrhea. Am. J. Chin. Med. 31, 321-326 https://doi.org/10.1142/S0192415X03001004
  5. Della Rocca, G. J., van Biesen, T., Daaka, Y., Luttrell, D. K., Luttrell, L. M., et al. (1997) Ras-dependent mitogenactivated protein kinase activation by G protein-coupled receptors. Convergence of Gi- and Gq-mediated pathways on calcium/calmodulin, Pyk2, and Src kinase. J. Biol. Chem. 272, 19125-19132 https://doi.org/10.1074/jbc.272.31.19125
  6. Gunther, S., Alexander, R. W., Atkinson, W. J., and Gimbrone, M. A. Jr. (1982) Functional angiotensin II receptors in cultured vascular smooth muscle cells. J. Cell Biol. 92, 289- 298 https://doi.org/10.1083/jcb.92.2.289
  7. Han, M. J., Kim, B. Y., Yoon, S. O., and Chung, A. S. (2003) Cell proliferation induced by reactive oxygen species is mediated via mitogen-activated protein kinase in chinese hamster lung fibroblast (V79) cells. Mol. Cells 15, 94-101
  8. Hong, Y., Hui, S. C., Chan, T. Y., and Hou, J. Y. (2002) Effect of berberine on regression of pressure-overload induced cardiac hypertrophy in rats. Am. J. Chin. Med. 30, 589-599 https://doi.org/10.1142/S0192415X02000612
  9. Iizuka, N., Oka, M., Yamamoto, K., Tangoku, A., Miyamoto, K., et al. (2003) Identification of common or distinct genes related to antitumor activities of a medicinal herb and its major component by oligonucleotide microarray. Int. J. Cancer 107, 666-672 https://doi.org/10.1002/ijc.11452
  10. Kang, D. G., Sohn, E. J., Kwon, E. K., Han, J. H., Oh, H., et al. (2002) Effects of berberine on angiotensin-converting enzyme and NO/cGMP system in vessels. Vascul. Pharmacol. 39, 281-286 https://doi.org/10.1016/S1537-1891(03)00005-3
  11. Kim, S. and Iwao, H. (2003) Stress and vascular responses: mitogen-activated protein kinases and activator protein-1 as promising therapeutic targets of vascular remodeling. J. Pharmacol. Sci. 91, 177-181 https://doi.org/10.1254/jphs.91.177
  12. Ko, W. H., Yao, X. Q., Lau, C. W., Law, W. I., Chen, Z. Y., et al. (2000) Vasorelaxant and antiproliferative effects of berberine. Eur. J. Pharmacol. 399, 187-196 https://doi.org/10.1016/S0014-2999(00)00339-3
  13. Kuo, C. L., Chi, C. W., and Liu, T. Y. (2004) The antiinflammatory potential of berberine in vitro and in vivo. Cancer Lett. 203, 127-137 https://doi.org/10.1016/j.canlet.2003.09.002
  14. Kohno, M., Yokokawa, K., Yasunari, K., Minami, M., Kano, H., et al. (1998) Induction by lysophosphatidylcholine, a major phospholipid component of atherogenic lipoproteins, of human coronary artery smooth muscle cell migration. Circulation 98, 353-359 https://doi.org/10.1161/01.CIR.98.4.353
  15. Kong, W., Wei, J., Abidi, P., Lin, M., Inaba, S., et al. (2004) Berberine is a novel cholesterol-lowering drug working through a unique mechanism distinct from statins. Nat. Med. 10, 1344-1351 https://doi.org/10.1038/nm1135
  16. Kugiyama, K., Sugiyama, S., Ogata, N., Oka, H., Doi, H., et al. (1999) Burst production of superoxide anion in human endothelial cells by lysophosphatidylcholine. Atherosclerosis 143, 201-204 https://doi.org/10.1016/S0021-9150(98)00288-3
  17. Lau, C. W., Yao, X. Q., Chen, Z. Y., Ko, W. H., and Huang, Y. (2001) Cardiovascular actions of berberine. Cardiovasc. Drug Rev. 19, 234-244 https://doi.org/10.1111/j.1527-3466.2001.tb00068.x
  18. Law, R. E., Meehan, W. P., Xi, X. P., Graf, K., Wuthrich, D. A., et al. (1996) Troglitazone inhibits vascular smooth muscle cell growth and intimal hyperplasia. J. Clin. Invest. 98, 1897-1905 https://doi.org/10.1172/JCI118991
  19. Martindale, J. L. and Holbrook, N. J. (2002) Cellular response to oxidative stress: signaling for suicide and survival. J. Cell. Physiol. 192, 1-15 https://doi.org/10.1002/jcp.10119
  20. Rivard, A. and Andres, V. (2000) Vascular smooth muscle cell proliferation in the pathogenesis of atherosclerotic cardiovascular diseases. Histol. Histopathol. 15, 557-571
  21. Stermitz, F. R., Lorenz, P., Tawara, J. N., Zenewicz, L. A., and Lewis, K. (2000) Synergy in a medicinal plant: antimicrobial action of berberine potentiated by 5′-methoxyhydnocarpin, a multidrug pump inhibitor. Proc. Natl. Acad. Sci. USA 97, 1433-1437
  22. Suenaga, H. and Kamata, K. (2003) Lysophosphatidylcholine activates extracellular-signal-regulated protein kinase and potentiates vascular contractile responses in rat aorta. J. Pharmacol. Sci. 92, 348-358 https://doi.org/10.1254/jphs.92.348
  23. Takemoto, M. and Liao, J. K. (2001) Pleiotropic effects of 3- hydroxy-3-methylglutaryl coenzyme a reductase inhibitors. Arterioscler. Thromb. Vasc. Biol. 21, 1712-1719 https://doi.org/10.1161/hq1101.098486
  24. Tarpey, M. M. and Fridovich, I. (2001) Methods of detection of vascular reactive species: nitric oxide, superoxide, hydrogen peroxide, and peroxynitrite. Circ. Res. 89, 224-236 https://doi.org/10.1161/hh1501.094365
  25. Wartenberg, M., Budde, P., De Marees, M., Grunheck, F., Tsang, S. Y., et al. (2003) Inhibition of tumor-induced angiogenesis and matrix-metalloproteinase expression in confrontation cultures of embryoid bodies and tumor spheroids by plant ingredients used in traditional Chinese medicine. Lab. Invest. 83, 87-98
  26. Watanabe, T., Pakala, R., Katagiri, T., and Benedict, C. R. (2002) Lysophosphatidylcholine is a major contributor to the synergistic effect of mildly oxidized low-density lipoprotein with endothelin-1 on vascular smooth muscle cell proliferation. J. Cardiovasc. Pharmacol. 39, 449-459 https://doi.org/10.1097/00005344-200203000-00017
  27. Yamakawa, T., Eguchi, S., Yamakawa, Y., Motley, E. D., Numaguchi, K., et al. (1998) Lysophosphatidylcholine stimulates MAP kinase activity in rat vascular smooth muscle cells. Hypertension 31, 248-253 https://doi.org/10.1161/01.HYP.31.1.248
  28. Yamakawa, T., Tanaka, S., Yamakawa, Y., Kamei, J., Numaguchi, K., et al. (2002) Lysophosphatidylcholine activates extracellular signal-regulated kinases 1/2 through reactive oxygen species in rat vascular smooth muscle cells. Arterioscler. Thromb. Vasc. Biol. 22, 752-758 https://doi.org/10.1161/01.ATV.0000015903.02749.71
  29. Yamakawa, T., Tanaka, S., Kamei, J., Kadonosono, K., and Okuda, K. (2003) Pitavastatin inhibits vascular smooth muscle cell proliferation by inactivating extracellular signalregulated kinases 1/2. J. Atheroscler. Thromb. 10, 37-42 https://doi.org/10.5551/jat.10.37
  30. Yla-Herttuala, S., Palinski, W., Rosenfeld, M. E., Parthasarathy, S., Carew, T. E., et al. (1989) Evidence for the presence of oxidatively modified low density lipoprotein in atherosclerotic lesions of rabbit and man. J. Clin. Invest. 84, 1086-1095 https://doi.org/10.1172/JCI114271
  31. Zeng, X. H., Zeng, X. J., and Li, Y. Y. (2003) Efficacy and safety of berberine for congestive heart failure secondary to ischemic or idiopathic dilated cardiomyopathy. Am. J. Cardiol. 92, 173-176 https://doi.org/10.1016/S0002-9149(03)00533-2