Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
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A Novel Urotensin II Receptor Antagonist, KR-36996 Inhibits Smooth Muscle Proliferation through ERK/ROS Pathway

  • Received : 2016.09.27
  • Accepted : 2016.10.27
  • Published : 2017.05.01
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Abstract

Urotensin II (UII) is a mitogenic and hypertrophic agent that can induce the proliferation of vascular cells. UII inhibition has been considered as beneficial strategy for atherosclerosis and restenosis. However, currently there is no therapeutics clinically available for atherosclerosis or restenosis. In this study, we evaluated the effects of a newly synthesized UII receptor (UT) antagonist, KR-36996, on the proliferation of SMCs in vitro and neointima formation in vivo in comparison with GSK-1440115, a known potent UT antagonist. In primary human aortic SMCs (HASMCs), UII (50 nM) induced proliferation was significantly inhibited by KR-36996 at 1, 10, and 100 nM which showed greater potency ($IC_{50}$: 3.5 nM) than GSK-1440115 ($IC_{50}$: 82.3 nM). UII-induced proliferation of HASMC cells was inhibited by U0126, an ERK1/2 inhibitor, but not by SP600125 (inhibitor of JNK) or SB202190 (inhibitor of p38 MAPK). UII increased the phosphorylation level of ERK1/2. Such increase was significantly inhibited by KR-36996. UII-induced proliferation was also inhibited by trolox, a scavenger for reactive oxygen species (ROS). UII-induced ROS generation was also decreased by KR-36996 treatment. In a carotid artery ligation mouse model, intimal thickening was dramatically suppressed by oral treatment with KR-36996 (30 mg/kg) which showed better efficacy than GSK-1440115. These results suggest that KR-36996 is a better candidate than GSK-1440115 in preventing vascular proliferation in the pathogenesis of atherosclerosis and restenosis.

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References

  1. Ames, R. S., Sarau, H. M., Chambers, J. K., Willette, R. N., Aiyar, N. V., Romanic, A. M., Louden, C. S., Foley, J. J., Sauermelch, C. F., Coatney, R. W., Ao, Z., Disa, J., Holmes, S. D., Stadel, J. M., Martin, J. D., Liu, W. S., Glover, G. I., Wilson, S., McNulty, D. E., Ellis, C. E., Elshourbagy, N. A., Shabon, U., Trill, J. J., Hay, D. W., Ohlstein, E. H., Bergsma, D. J. and Douglas, S. A. (1999) Human urotensin-II is a potent vasoconstrictor and agonist for the orphan receptor GPR14. Nature 401, 282-286. https://doi.org/10.1038/45809
  2. Behm, D. J., Aiyar, N. V., Olzinski, A. R., McAtee, J. J., Hilfiker, M. A., Dodson, J. W., Dowdell, S. E., Wang, G. Z., Goodman, K. B., Sehon, C. A., Harpel, M. R., Willette, R. N., Neeb, M. J., Leach, C. A. and Douglas, S. A. (2010) GSK1562590, a slowly dissociating urotensin-II receptor antagonist, exhibits prolonged pharmacodynamic activity ex vivo. Br. J. Pharmacol. 161, 207-228. https://doi.org/10.1111/j.1476-5381.2010.00889.x
  3. Behm, D. J., McAtee, J. J., Dodson, J. W., Neeb, M. J., Fries, H. E., Evans, C. A., Hernandez, R. R., Hoffman, K. D., Harrison, S. M., Lai, J. M., Wu, C., Aiyar, N. V., Ohlstein, E. H. and Douglas, S. A. (2008) Palosuran inhibits binding to primate UT receptors in cell membranes but demonstrates differential activity in intact cells and vascular tissues. Br. J. Pharmacol. 155, 374-386.
  4. Chen, Y. L., Liu, J. C., Loh, S. H., Chen, C. H., Hong, C. Y., Chen, J. J. and Cheng, T. H. (2008) Involvement of reactive oxygen species in urotensin II-induced proliferation of cardiac fibroblasts. Eur. J. Pharmacol. 593, 24-29. https://doi.org/10.1016/j.ejphar.2008.07.025
  5. Djordjevic, T., BelAiba, R. S., Bonello, S., Pfeilschifter, J., Hess, J. and Gorlach, A. (2005) Human urotensin II is a novel activator of NADPH oxidase in human pulmonary artery smooth muscle cells. Arterioscler. Thromb. Vasc. Biol. 25, 519-525. https://doi.org/10.1161/01.ATV.0000154279.98244.eb
  6. Duran-Prado, M., Morell, M., Delgado-Maroto, V., Castano, J. P., Aneiros-Fernandez, J., de Lecea, L., Culler, M. D., Hernandez-Cortes, P., O'Valle, F. and Delgado, M. (2013) Cortistatin inhibits migration and proliferation of human vascular smooth muscle cells and decreases neointimal formation on carotid artery ligation. Circ. Res. 112, 1444-1455. https://doi.org/10.1161/CIRCRESAHA.112.300695
  7. Ferguson, D., Koo, J. W., Feng, J., Heller, E., Rabkin, J., Heshmati, M., Renthal, W., Neve, R., Liu, X., Shao, N., Sartorelli, V., Shen, L. and Nestler, E. J. (2013) Essential role of SIRT1 signaling in the nucleus accumbens in cocaine and morphine action. J. Neurosci. 33, 16088-16098. https://doi.org/10.1523/JNEUROSCI.1284-13.2013
  8. Heringlake, M., Kox, T., Uzun, O., Will, B., Bahlmann, L., Klaus, S., Eleftheriadis, S., Armbruster, F. P., Franz, N. and Kraatz, E. (2004) The relationship between urotensin II plasma immunoreactivity and left ventricular filling pressures in coronary artery disease. Regul. Pept. 121, 129-136. https://doi.org/10.1016/j.regpep.2004.04.012
  9. Huang, J., Zhang, J., Pathak, A., Li, J. and Stouffer, G. A. (2011) Perivascular delivery of blebbistatin reduces neointimal hyperplasia after carotid injury in the mouse. J. Pharmacol. Exp. Ther. 336, 116-126. https://doi.org/10.1124/jpet.110.174615
  10. Lee, B. K. and Jung, Y. S. (2012) The $Na^+/H^+$ exchanger-1 inhibitor cariporide prevents glutamate-induced necrotic neuronal death by inhibiting mitochondrial $Ca^{2+}$ overload. J. Neurosci. Res. 90, 860-869. https://doi.org/10.1002/jnr.22818
  11. Lee, K., Yim, J. H., Lee, H. K. and Pyo, S. (2016) Inhibition of VCAM-1 expression on mouse vascular smooth muscle cells by lobastin via downregulation of p38, ERK 1/2 and $NF-{\kappa}B$ signaling pathways. Arch. Pharm. Res. 39, 83-93. https://doi.org/10.1007/s12272-015-0687-3
  12. Lee, N. Y., Rieckmann, P. and Kang, Y. S. (2012) The changes of P-glycoprotein activity by interferon-$\gamma$ and tumor necrosis factor-$\alpha$ in primary and immortalized human brain microvascular endothelial cells. Biomol. Ther. (Seoul) 20, 293-298. https://doi.org/10.4062/biomolther.2012.20.3.293
  13. Liang, Q., Yu, F., Cui, X., Duan, J., Wu, Q., Nagarkatti, P. and Fan, D. (2013) Sparstolonin B suppresses lipopolysaccharide-induced inflammation in human umbilical vein endothelial cells. Arch. Pharm. Res. 36, 890-896. https://doi.org/10.1007/s12272-013-0120-8
  14. Loirand, G., Rolli-Derkinderen, M. and Pacaud, P. (2008) Urotensin II and atherosclerosis. Peptides 29, 778-782. https://doi.org/10.1016/j.peptides.2007.08.024
  15. Louis, S. F. and Zahradka, P. (2010) Vascular smooth muscle cell motility: From migration to invasion. Exp. Clin. Cardiol. 15, e75-e85.
  16. Ou, Y., Li, Q., Wang, J., Li, K. and Zhou, S. (2014) Antitumor and apoptosis induction effects of paeonol on mice bearing EMT6 breast carcinoma. Biomol. Ther. (Seoul) 22, 341-346. https://doi.org/10.4062/biomolther.2013.106
  17. Park, S. L., Lee, B. K., Kim, Y. A., Lee, B. H. and Jung, Y. S. (2013) Inhibitory effect of an urotensin II receptor antagonist on proinflammatory activation induced by urotensin II in human vascular endothelial cells. Biomol. Ther. (Seoul) 21, 277-283. https://doi.org/10.4062/biomolther.2013.051
  18. Pendyala, S., Usatyuk, P. V., Gorshkova, I. A., Garcia, J. G. and Natarajan, V. (2009) Regulation of NADPH oxidase in vascular endothelium: the role of phospholipases, protein kinases, and cytoskeletal proteins. Antioxid. Redox Signal. 11, 841-860. https://doi.org/10.1089/ars.2008.2231
  19. Rakowski, E., Hassan, G. S., Dhanak, D., Ohlstein, E. H., Douglas, S. A. and Giaid, A. (2005) A role for urotensin II in restenosis following balloon angioplasty: use of a selective UT receptor blocker. J. Mol. Cell. Cardiol. 39, 785-791. https://doi.org/10.1016/j.yjmcc.2005.07.002
  20. Rudijanto, A. (2007) The role of vascular smooth muscle cells on the pathogenesis of atherosclerosis. Acta Med. Indones. 39, 86-93.
  21. Sauzeau, V., Le Mellionnec, E., Bertoglio, J., Scalbert, E., Pacaud, P. and Loirand, G. (2001) Human urotensin II-induced contraction and arterial smooth muscle cell proliferation are mediated by RhoA and Rho-kinase. Circ. Res. 88, 1102-1104. https://doi.org/10.1161/hh1101.092034
  22. Sindermann, J. R., Smith, J., Kobbert, C., Plenz, G., Skaletz-Rorowski, A., Solomon, J. L., Fan, L. and March, K. L. (2002) Direct evidence for the importance of p130 in injury response and arterial remodeling following carotid artery ligation. Cardiovasc. Res. 54, 676-683. https://doi.org/10.1016/S0008-6363(02)00272-9
  23. Suguro, T., Watanabe, T., Ban, Y., Kodate, S., Misaki, A., Hirano, T., Miyazaki, A. and Adachi, M. (2007) Increased human urotensin II levels are correlated with carotid atherosclerosis in essential hypertension. Am. J. Hypertens. 20, 211-217. https://doi.org/10.1016/j.amjhyper.2006.08.001
  24. Tsoukas, P., Kane, E. and Giaid, A. (2011) Potential clinical implications of the urotensin II receptor antagonists. Front. Pharmacol. 2, 38.
  25. Watanabe, T., Arita, S., Shiraishi, Y., Suguro, T., Sakai, T., Hongo, S. and Miyazaki, A. (2009) Human urotensin II promotes hypertension and atherosclerotic cardiovascular diseases. Curr. Med. Chem. 16, 550-563. https://doi.org/10.2174/092986709787458515

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