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http://dx.doi.org/10.4062/biomolther.2014.012

The Inhibitory Effect of Apigenin on the Agonist-Induced Regulation of Vascular Contractility via Calcium Desensitization-Related Pathways  

Je, Hyun Dong (Department of Pharmacology, College of Pharmacy, Catholic University of Daegu)
Kim, Hyeong-Dong (Department of Physical Therapy, College of Health Science, Korea University)
La, Hyen-Oh (Department of Pharmacology, College of Medicine, The Catholic University of Korea)
Publication Information
Biomolecules & Therapeutics / v.22, no.2, 2014 , pp. 100-105 More about this Journal
Abstract
Apigenin, a natural flavonoid found in a variety of vegetables and fruits, has been shown to possess many biological functions. The present study was undertaken to investigate the influence of apigenin on vascular smooth muscle contractility and to determine the mechanism involved. Denuded aortic rings from male rats were used and isometric contractions were recorded and combined with molecular experiments. Apigenin significantly relaxed fluoride-, thromboxane $A_2$ mimetic- or phorbol ester-induced vascular contraction, which suggests that apigenin could be an anti-hypertensive that reduces agonist-induced vascular contraction regardless of endothelial nitric oxide synthesis. Furthermore, apigenin significantly inhibited fluoride-induced increases in pMYPT1 levels and phorbol ester-induced increases in pERK1/2 levels, which suggests the mechanism involving the inhibition of Rho-kinase and MEK activity and the subsequent phosphorylation of MYPT1 and ERK1/2. This study provides evidence regarding the mechanism underlying the relaxation effect of apigenin on agonist-induced vascular contraction regardless of endothelial function.
Keywords
Apigenin; ERK1/2; Fluoride; MYPT1; Phorbol ester; Rho-kinase;
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1 Zhang, Y. H., Park, Y. S., Kim, T. J., Fang, L. H., Ahn, H. Y., Hong, J. T., Kim, Y., Lee, C. K. and Yun, Y. P. (2000) Endothelium-dependent vasorelaxant and antiproliferative effects of apigenin. Gen. Pharmacol. 35, 341-347.   DOI   ScienceOn
2 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
3 Somlyo, A. P. and Somlyo, A. V. (1994) Signal transduction and regulation in smooth muscle. Nature 372, 231-236.   DOI   ScienceOn
4 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
5 Touyz, R. M., Deng, L. Y., He, G., Wu, X. H. and Schiffrin, E. L. (1999) Angiotensin II stimulates DNA and protein synthesis in vascular smooth muscle cells from human arteries: role of extracellular signal-regulated kinases. J. Hypertens. 17, 907-916.   DOI   ScienceOn
6 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
7 Uehata, M., Ishizaki, T., Satoh, H., Ono, T., Kawahara, T., Morishita, T., Tamakawa, H., Yamagami, K., Inui, J., Maekawa, M. and Narumiya, S. (1997) Calcium sensitization of smooth muscle mediated by a Rho-associated protein kinase in hypertension. Nature 389, 990-994.   DOI   ScienceOn
8 Wang, W., Heideman, L., Chung, C. S., Pelling, J. C., Koehler, K. J. and Birt, D. F. (2000) Cell-cycle arrest at G2/M and growth inhibition by apigenin in human colon carcinoma cell lines. Mol. Carcinog. 28, 102-110.   DOI   ScienceOn
9 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.
10 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
11 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
12 Xu, Q., Liu, Y., Gorospe, M., Udelsman, R. and Holbrook, N. J. (1996) Acute hypertension activates mitogen-activated protein kinases in arterial wall. J. Clin. Invest. 97, 508-514.   DOI
13 Caltagirone, S., Rossi, C., Poggi, A., Ranelletti, F. O., Natali, P. G., Brunetti, M., Aiello, F. B. and Piantelli, M. (2000) Flavonoids apigenin and quercetin inhibit melanoma growth and metastatic potential. Int. J. Cancer 87, 595-600.   DOI   ScienceOn
14 Fotsis, T., Pepper, M. S., Montesano, R., Aktas, E., Breit, S., Schweigerer, L., Rasku, S., Wahala, K. and Adlercreutz, H. (1998) Phytoestrogens and inhibition of angiogenesis. Baillieres Clin. Endocrinol. Metab. 12, 649-666.   DOI   ScienceOn
15 Gu, Z., Kordowska, J., Williams, G. L., Wang, C. L. and Hai, C. M. (2007) Erk1/2 MAPK and caldesmon differentially regulate podosome dynamics in A7r5 vascular smooth muscle cells. Exp. Cell Res. 313, 849-866.   DOI
16 Kordowska, J., Huang, R. and Wang, C. L. (2006) Phosphorylation of caldesmon during smooth muscle contraction and cell migration or proliferation. J. Biomed. Sci. 13, 159-172.   DOI
17 Han, J. Y., Ahn, S. Y., Kim, C. S., Yoo, S. K., Kim, S. K., Kim, H. C., Hong, J. T. and Oh, K. W. (2012) Protection of apigenin against kainate-induced excitotoxicity by anti-oxidative effects. Biol. Pharm. Bull. 35, 1440-1446.   DOI
18 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
19 Kitazawa, T., Masuo, M. and Somlyo, A. P. (1991) G-protein-mediated inhibition of myosin light-chain phosphatase in vascular smooth muscle. Proc. Natl. Acad. Sci. U.S.A. 88, 9307-9310.   DOI   ScienceOn
20 Nicholas, C., Batra, S., Vargo, M. A., Voss, O. H., Gavrilin, M. A., Wewers, M. D., Guttridge, D. C., Grotewold, E. and Doseff, A. I. (2007) Apigenin blocks lipopolysaccharide-induced lethality in vivo and proinflammatory cytokines expression by inactivating NF-${\kappa}B$ through the suppression of p65 phosphorylation. J. Immunol. 179, 7121-7127.   DOI
21 Peterson, J. and Dwyer, J. (1988) Flavonoids: dietary occurrence and biochemical activity. Nutr. Res. 18, 1995-2018.
22 Rotondo, A., Serio, R. and Mule, F. (2009) Gastric relaxation induced by apigenin and quercetin: analysis of the mechanism of action. Life Sci. 85, 85-90.   DOI