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http://dx.doi.org/10.1007/s10059-009-0052-9

Inhibitory Effect of Genistein on Agonist-Induced Modulation of Vascular Contractility  

Je, Hyun Dong (Department of Pharmacology, College of Pharmacy, Catholic University of Daegu)
Sohn, Uy Dong (College of Pharmacy, Chung Ang University)
Publication Information
Molecules and Cells / v.27, no.2, 2009 , pp. 191-198 More about this Journal
Abstract
The present study was undertaken to determine whether treatment with genistein, the plant-derived estrogen-like compound influences agonist-induced vascular smooth muscle contraction and, if so, to investigate related mechanisms. The measurement of isometric contractions using a computerized data acquisition system was combined with molecular experiments. Genistein completely inhibited KCl-, phorbol ester-, phenylephrine-, fluoride- and thromboxane $A_2$-induced contractions. An inactive analogue, daidzein, completely inhibited only fluoride-induced contraction regardless of endothelial function, suggesting some difference between the mechanisms of RhoA/Rho-kinase activators such as fluoride and thromboxane $A_2$. Furthermore, genistein and daidzein each significantly decreased phosphorylation of MYPT1 at Thr855 had been induced by a thromboxane $A_2$ mimetic. Interestingly, iberiotoxin, a blocker of large-conductance calcium-activated potassium channels, did not inhibit the relaxation response to genistein or daidzein in denuded aortic rings precontracted with fluoride. In conclusion, genistein or daidzein elicit similar relaxing responses in fluoride-induced contractions, regardless of tyrosine kinase inhibition or endothelial function, and the relaxation caused by genistein or daidzein was not antagonized by large conductance $K_{Ca}$-channel inhibitors in the denuded muscle. This suggests that the RhoA/Rho-kinase pathway rather than $K^+$- channels are involved in the genistein-induced vasodilation. In addition, based on molecular and physiological results, only one vasoconstrictor fluoride seems to be a full RhoA/Rho-kinase activator; the others are partial activators.
Keywords
$Ca^{2+}$-activated $K^+$ channels; fluoride; MYPT1; Rho-kinase; thromboxane $A_2$ mimetic; tyrosine kinase; vasodilation;
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1 Akiyama, T., Ishida, J., Nakagawa, S., Ogawara, H., Watanabe, S., Itoh, N., Shibuya, M., and Fukami, Y. (1987). Genistein, a specific inhibitor of tyrosine-specific protein kinases. J. Biol. Chem. 262, 5592-5595
2 Anthony, M.S. (2002). Phytoestrogens and cardiovascular disease: where's the meat? Arterioscler. Thromb. Vasc. Bio. 22, 1245-1247   DOI   ScienceOn
3 Deng, J.T., Van Lierop, J.E., Sutherland, C., and Walsh, M.P. (2001). $Ca^{2+}$-independent smooth muscle contraction: a novel function for integrin-linked kinase. J. Biol. Chem. 276, 16365-16373   DOI   ScienceOn
4 Edwards, G., and Weston, A. (1995). Pharmacology of the potassium channel openers. Cardiovasc. Drugs Ther. 9, 185-193   DOI   ScienceOn
5 Martin, P.M., Horwitz, K.B., Ryan, D.S., and McGuire, W.L. (1978). Phytoestrogen interaction with estrogen receptors in human breast cancer cells. Endocrinology 103, 1860-1867   DOI   ScienceOn
6 Murphy, R.A. (1982). Myosin phosphorylation and crossbridge regulation in arterial smooth muscle. Hypertension 4, 3-7   PUBMED
7 Noda, M., Yasuda-Fukazawa, C., Moriishi, K., Kato, T., Okuda, T., Kurokawa, K., and Takuwa, Y. (1995). Involvement of rho in GTP gamma S-induced enhancement of phosphorylation of 20 kDa myosin light chain in vascular smooth muscle cells: inhibition of phosphatase activity. FEBS Lett. 367, 246-250   DOI   ScienceOn
8 Somlyo, A.P., and Somlyo, A.V. (1994). Signal transduction and regulation in smooth muscle. Nature 372, 231-236   DOI   ScienceOn
9 Somlyo, A.P., and Somlyo, A.V. (1998). From pharmacomechanical coupling to G-proteins and myosin phosphatase. Acta. Physiol. Scand. 164, 437-448   DOI   ScienceOn
10 Tsai, M.H., and Jiang, M.J. (2006). Rho-kinase-mediated regulation of receptor-agonist-stimulated smooth muscle contraction. Pflugers Arch. 453, 223-232   DOI   ScienceOn
11 Wier, W.G., and Morgan, K.G. (2003). $\alpha$1-Adrenergic signaling mechanisms in contraction of resistance arteries. Rev. Physiol. Biochem. Pharmacol. 150, 91-139
12 Nakao, F., Kobayashi, S., Mogami, K., Mizukami, Y., Shirao, S., Miwa, S., Todoroki-Ikebe, N., Ito, M., and Matsuzaki, M. (2002). Involvement of Src family protein tyrosine kinases in $Ca^{2+}$+ sensitization of coronary artery contraction mediated by a sphingosylphosphorylcholine-Rho-kinase pathway. Circ. Res. 91, 953-960   DOI   ScienceOn
13 Pfitzer, G. (2001). Invited reviews: regulation of myosin light chain phosphorylation in smooth muscle. J. Appl. Physiol. 91, 497-503   DOI
14 Delclos, K.B., Bucci, T.J., Lomax, L.G., Latendresse, J.R., Warbritton, A., Weis, C.C., and Newbold, R.R. (2001). Effects of dietary genistein exposure during development on male and female CD (Sprague-Dawley) rats. Reprod Toxicol 15, 647-663   DOI   ScienceOn
15 Hsieh, C.Y., Santell, R.C., Haslam, S.Z., and Helferich, W.G. (1998). Estrogenic effects of genistein on the growth of estrogen receptor-positive human breast cancer (MCF-7) cells in vitro and in vivo. Cancer Res. 58, 3833-3838
16 Jones, S.V. (2003) Role of the small GTPase Rho in modulation of the inwardly rectifying potassium channel Kir2.1. Mol. Pharmacol. 64, 987-993   DOI   PUBMED   ScienceOn
17 Kyselova, V., Peknicova, J., Boubelik, M., and Buckiova, D. (2004). Body and organ weight, sperm acrosomal status and reproduction after genistein and diethylstilbestrol treatment of CD1 mice in a multigenerational study. Theriogenology 61, 1307-1325   DOI   ScienceOn
18 Nelson, M.T., and Quayle, J.M. (1995). Physiological roles and properties of potassium channels in arterial smooth muscle. Am. J. Physiol. 268, 799-822   DOI
19 Wilson, D.P., Susnjar, M., Kiss, E., Sutherland, C., and Walsh, M.P. (2005). Thromboxane $A_2$-induced contraction of rat caudal arterial smooth muscle involves activation of $Ca^{2+}$ entry and $Ca^{2+}$ sensitization: Rho-associated kinase-mediated phosphorylation of MYPT1 at Thr-855, but not Thr-697. Biochem. J. 389, 763-774   DOI   ScienceOn
20 Muranyi, A., MacDonald, J.A., Deng, J.T., Wilson, D.P., Haystead, T.A., Wlash, M.P., Erdodi, F., Kiss, E., Wu, Y., and Hartshorne, D.J. (2002). Phosphorylation of the myosin phosphatase target subunit by integrin-linked kinase. Biochem. J. 366, 211-216   DOI
21 Wooldridge, A.A., MacDonald, J.A., Erdodi, F., Ma, C., Borman, M.A., Hartshorne, D.J., and Haystead, T.A. (2004). Smooth muscle phosphatase is regulated in vivo by exclusion of phosphorylation of threonine 696 of MYPT1 by phosphorylation of Serine 695 in response to cyclic nucleotides. J. Biol. Chem. 279, 34496-34504   DOI   ScienceOn
22 Sacks, F.M., Lichtenstein, A., Van Horn, L., Harris, W., Kris-Etherton, P., and Winston, M. (2006). Soy protein, isoflavones, and cardiovascular health: an American heart association science advisory for professionals from the nutrition committee. Circulation 113, 1034-1044   DOI   ScienceOn
23 Shenolikar, S., and Nairn, A.C. (1991). Protein phosphatases: recent progress. Adv. Second Messenger Phosphoprotein Res. 23, 1-121
24 Storey, N.M., O'Bryan, J.P., and Armstrong, D.L. (2002). Rac and Rho mediate opposing hormonal regulation of the ether-a-gogo-related potassium channels. Curr. Biol. 12, 27-33   DOI   ScienceOn
25 Kanaho, Y., Moss, J., and Vaughan, M. (1985) Mechanism of inhibition of transducin GTPase activity by fluoride and aluminum. J. Biol. Chem. 260, 11493-11497
26 Cockcroft, S., and Taylor, J.A. (1987). Fluoroaluminates mimic guanosine 5'-[gamma-thio]triphosphate in activating the poly-phosphoinositide phosphodiesterase of hepatocyte membranes. Role for the guanine nucleotide regulatory protein Gp in signal transduction. Biochem. J. 241, 409-414   DOI
27 Kuiper, G.G., Lemmen, J.G., Carlsson, B., Corton, J.C., Safe, S.H., Van der Saag, P.T., Van der Burg, B., and Gustafsson, J.A. (1998) Interaction of estrogenic chemicals and phytoestrogens with estrogen receptor beta. Endocrinology 139, 4252-4263   DOI   ScienceOn
28 Luykenaar, K.D., Brett, S.E., Wu, B.N., Wiehler, W.B., and Welsh, D.G. (2004). Pyrimidine nucleotides suppress KDR currents and depolarize rat cerebral arteries by activating Rho kinase. Am. J. Phyiol. Heart Circ. Physiol. 286, H1088-H1100   DOI
29 Sakurada, S., Takuwa, N., Sugimoto, N., Wang, Y., Seto, M., Sasaki, Y., and Takuwa, Y. (2003). $Ca^{2+}$-dependent activation of Rho and Rho-kinase in membrane depolarization-induced and receptor stimulation-induced vascular smooth muscle contraction. Circ. Res. 93, 548-556   DOI   ScienceOn
30 Hodgson, J.M., Croft, K.D., Puddey, L.B., Mori, T.A., and Beilin, L.J. (1996). Soybean isoflavonoids and their metabolic products inhibit in vitro lipoprotein oxidation in serum. J. Nutr. Biochem. 7, 664-669   DOI   ScienceOn
31 Uehata, M., Ishizaki, T., Satoh, H., Ono, T., Kawahara, T., Morishita, T., Tamakawa, H., Yamagami, K., Inui, J., Maekawa, M., and et al. (1997). Calcium sensitization of smooth muscle mediated by a Rho-associated protein kinase in hypertension. Nature 389, 990-994   DOI   ScienceOn
32 Wang, J., Eltoum, I.E., and Lamartiniere, C.A. (2004). Genistein alters growth factor signaling in transgenic prostate model (TRAMP). Mol. Cell. Endocrinol. 219, 171-180   DOI   ScienceOn
33 Tasaki, K., Hori, M., Ozaki, H., Karaki, H., and Wakabayashi, I. (2003). Difference in signal transduction mechanisms involved in 5-hydroxytryptamine- and U46619-induced vasoconstrictions. J. Smooth. Muscle Res. 39, 107-117   DOI   ScienceOn
34 Kitazawa, T., Masuo, M., and Somlyo, A.P. (1991). Proteinmediated inhibition of myosin light-chain phosphatase in vascular smooth muscle. Proc. Natl. Acad. Sci. USA 88, 9307-9310   DOI   ScienceOn
35 Amano, M., Ito, M., Kimura, K., Fukata, Y., Chihara, K., Nakano, T., Matsuura, Y., and Kaibuchi, K. (1996). Phosphorylation and activation of myosin by Rho-associated kinase (Rho-kinase). J. Biol. Chem. 271, 20246-20249   DOI   ScienceOn
36 Jeon, S.B., Jin, F., Kim, J.I., Kim, S.H., Suk, K., Chae, S.C., Jun, J.E., Park, W.H., and Kim, I.K. (2006). A role for Rho kinase in vascular contraction evoked by sodium fluoride. Biochem. Biophys. Res. Commun. 343, 27-33   DOI   ScienceOn
37 Shimizu, M., and Weinstein, I.B. (2005). Modulation of signal transduction by tea cathechins and related phytochemicals. Mutat. Res. 591, 147-160   DOI
38 Wisniewski, A.B., Klein, S.L., Lakshmanan, Y., and Gearhart, J.P. (2003). Exposure to genistein during gestation and lactation demasculinizes the reproductive system in rats. J. Urol. 169, 1582–1586   DOI   ScienceOn
39 Anderson, J.W., Johnstone, B.W., and Cook-Newell, M.E. (1995). Meta-analysis of the effects of soy protein intake on serum lipids. N. Engl. J. Med. 333, 276-282   DOI   ScienceOn
40 Davis, M.J., Wu, X., Nurkiewicz, T.R., Kawasaki, J., Gui, P., Hill, M.A., and Wilson, E. (2001). Regulation of ion channels by protein tyrosine phosphorylation. Am. J. Physiol. 281, H1835-H1862
41 Gilman, A.G. (1984). Guanine nucleotide-binding regulatory proteins and dual control of adenylate cyclase. J. Clin. Invest. 73, 1-4   DOI   ScienceOn
42 Somlyo, A.P., and Somlyo, A.V. (2000). Signal transduction by Gproteins, rho-kinase and protein phosphatase to smooth muscle and non-muscle myosin II. J. Physiol. 522, 177-185   DOI   ScienceOn
43 Bigay, J., Deterre, P., Pfister, C., and Chabre, M. (1985). Fluoro-aluminates activate transducin-GDP by mimicking the gamma-phosphate of GTP in its binding site. FEBS Lett. 191, 181-185   DOI   ScienceOn
44 Blackmore, P.F., and Exton, J.H. (1986). Studies on the hepatic calcium-mobilizing activity of aluminum fluoride and glucagon. Modulation by cAMP and phorbol myristate acetate. J. Biol. Chem. 261, 11056-11063
45 Watts, S.W., Yeum, C.H., Campbell, G., and Webb, R.C. (1996). Serotonin stimulates protein tyrosyl phosphorylation and vascular contraction via tyrosine kinase. J. Vasc. Res. 33, 288-298   DOI   ScienceOn
46 Nobes, C.D., Hawkins, P., Stephens, L., and Hall, A. (1995). Activation of the small GTP-binding proteins rho and rac by growth factor receptors. J. Cell Sci. 108, 225-233
47 Zeng, Y.Y., Benishin, C.G., and Pang, P.K. (1989). Guanine nucleotide binding proteins may modulate gating of calcium channels in vascular smooth muscle. I. Studies with fluoride. J. Pharmacol. Exp. Ther. 250, 343-351
48 Finn, H.M., and Ridley, A.J. (1996). Rho stimulates tyrosine phosphorylation of focal adhesion kinase p130 and paxillin. J. Cell. Sci. 109, 1133-1141
49 Nobe, K., and Paul, R.J. (2001). Distinct pathways of $Ca^{2+}$ sensitization in porcine coronary artery: effects of Rho-related kinase and protein kinase C inhibition on force and intracellular $Ca^{2+}$. Circ. Res. 88, 1283-1290   DOI   ScienceOn
50 Squadrito, F., Altavilla, D., Morabito, N., Crisafulli, A., D'Anna, R., Corrado, F., Ruggeri, P., Campo, G. M., Calapai, G., Caputi, A.P., and Squadrito, G. (2002). The effect of the phytoestrogen genistein on plasma nitric oxide concentrations, endothelin-1 levels and endothelium dependent vasodilation in postmenopausal women. Atherosclerosis 163, 339-347   DOI   ScienceOn
51 Liu, C.Y., and Sturek, M. (1996). Attenuation of endothelin-1-induced calcium response by tyrosine kinase inhibitors in vascular smooth muscle cells. Am. J. Physiol. 270, C1825-C1833   DOI
52 Cachero, T.G., Morielli, A.D., and Peralta, E.G. (1998). The small GTP-binding protein RhoA regulates a delayed rectifier potassium channel. Cell 93, 1077-1085   DOI   ScienceOn
53 Mitchell, J.H., and Collins, A.R. (1999). Effects of a soymilk supplement on plasma cholesterol levels and oxidative DNA damage in men-a pilot study. Eur. J. Nutr. 38, 143-148   DOI   ScienceOn
54 Rathel, T.R., Leikert, J.F., Vollmar, A.M., and Dirsch, V.M. (2005). The soy isoflavone genistein induces a late but sustained activation of the endothelial nitric oxide-synthase system in vitro. Brit. J. Pharmacol. 144, 394-399   DOI   ScienceOn
55 Chabre, M. (1990). Aluminofluoride and beryllofluoride complexes: a new phosphate analogs in enzymology. Trends Biochem. Sci. 15, 6-10   DOI   PUBMED   ScienceOn
56 Low, A.M. (1996). Role of tyrosine kinase on $Ca^{2+}$ entry and refilling of agonist-sensitive $Ca^{2+}$ stores in vascular smooth muscles. Can. J. Physiol. Pharmacol. 74, 298-304   DOI   PUBMED   ScienceOn