Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
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Endothelin Receptor Overexpression Alters Diastolic Function in Cultured Rat Ventricular Myocytes

  • Kang, Mi-Suk (Molecular and Cellular Pharmacology, University of Wisconsin) ;
  • Walker, Jeffery W. (Molecular and Cellular Pharmacology, University of Wisconsin) ;
  • Chung, Ka-Young (Molecular and Cellular Pharmacology, University of Wisconsin)
  • Received : 2012.05.16
  • Accepted : 2012.06.18
  • Published : 2012.07.31
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Abstract

The endothelin (ET) signaling pathway controls many physiological processes in myocardium and often becomes upregulated in heart diseases. The aim of the present study was to investigate the effects of ET receptor upregulation on the contractile function of adult ventricular myocytes. Primary cultured adult rat ventricular myocytes were used as a model system of ET receptor overexpression in the heart. Endothelin receptor type A ($ET_A$) or type B ($ET_B$) was overexpressed by Adenoviral infection, and the twitch responses of infected ventricular myocytes were measured after ET-1 stimulation. Overexpression of $ET_A$ exaggerated positive inotropic effect (PIE) and diastolic shortening of ET-1, and induced a new twitch response including twitch broadening. On the contrary, overexpression of $ET_B$ increased PIE of ET-1, but did not affect other two twitch responses. Control myocytes expressing endogenous receptors showed a parallel increase in twitch amplitude and systolic $Ca^{2+}$ in response to ET-1. However, intracellular $Ca^{2+}$ did not change in proportion to the changes in contractility in myocytes overexpressing $ET_A$. Overexpression of $ET_A$ enhanced both systolic and diastolic contractility without parallel changes in $Ca^{2+}$. Differential regulation of this nature indicates that upregulation of $ET_A$ may contribute to diastolic myocardial dysfunction by selectively targeting myofilament proteins that regulate resting cell length, twitch duration and responsiveness to prevailing $Ca^{2+}$.

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References

  1. Asano, K., Bohlmeyer, T. J., Westcott, J. Y., Zisman, L., Kinugawa, K., Good, M., Minobe, W. A., Roden, R., Wolfel, E. E., Lindenfeld, J., David Port, J., Perryman, M. B., Clevel, J., Lowes, B. D. and Bristow, M. R. (2002) Altered expression of endothelin receptors in failing human left ventricles. J. Mol. Cell Cardiol. 34, 833-846. https://doi.org/10.1006/jmcc.2002.2022
  2. Aurigemma, G. P., Zile, M. R. and Gaasch, W. H. (2006) Contractile behavior of the left ventricle in diastolic heart failure: with emphasis on regional systolic function. Circulation 113, 296-304. https://doi.org/10.1161/CIRCULATIONAHA.104.481465
  3. Cheng, C. P., Ukai, T., Onishi, K., Ohte, N., Suzuki, M., Zhang, Z. S., Cheng, H. J., Tachibana, H., Igawa, A. and Little, W. C. (2001) The role of ANG II and endothelin-1 in exercise-induced diastolic dysfunction in heart failure. Am. J. Physiol. Heart Circ. Physiol. 280, H1853-1860. https://doi.org/10.1152/ajpheart.2001.280.4.H1853
  4. Chopra, M. and Sharma, A. C. (2007) Distinct cardiodynamic and molecular characteristics during early and late stages of sepsisinduced myocardial dysfunction. Life Sci. 81, 306-316. https://doi.org/10.1016/j.lfs.2007.05.021
  5. Chung, K. Y., Kang, M. and Walker, J. W. (2008) Contractile regulation by overexpressed ETA requires intact T tubules in adult rat ventricular myocytes. Am. J. Physiol. Heart Circ. Physiol. 294, H2391-2399. https://doi.org/10.1152/ajpheart.00011.2008
  6. Ebihara, Y., Haist, J. V. and Karmazyn, M. (1996) Modulation of endothelin- 1 effects on rat hearts and cardiomyocytes by nitric oxide and 8-bromo cyclic GMP. J. Mol. Cell Cardiol. 28, 265-277. https://doi.org/10.1006/jmcc.1996.0025
  7. Endoh, M., Fujita, S., Yang, H. T., Talukder, M. A., Maruya, J. and Norota, I. (1998) Endothelin: receptor subtypes, signal transduction, regulation of $Ca^{2+}$ transients and contractility in rabbit ventricular myocardium. Life Sci. 62, 1485-1489. https://doi.org/10.1016/S0024-3205(98)00094-0
  8. Evans, H. G., Lewis, M. J. and Shah, A. M. (1994) Modulation of myocardial relaxation by basal release of endothelin from endocardial endothelium. Cardiovasc. Res. 28, 1694-1699. https://doi.org/10.1093/cvr/28.11.1694
  9. Goldberg, A. T., Bond, B. R., Mukherjee, R., New, R. B., Zellner, J. L., Crawford, F. A. Jr. and Spinale, F. G. (2000) Endothelin receptor pathway in human left ventricular myocytes: relation to contractility. Ann. Thorac. Surg. 69, 711-715. https://doi.org/10.1016/S0003-4975(99)01515-5
  10. Hasegawa, K., Fujiwara, H., Koshiji, M., Inada, T., Ohtani, S., Doyama, K., Tanaka, M., Matsumori, A., Fujiwara, T., Shirakami, G., Hosoda, K., Nakao, K. and Sasayama, S. (1996) Endothelin-1 and its receptor in hypertrophic cardiomyopathy. Hypertension 27, 259-264. https://doi.org/10.1161/01.HYP.27.2.259
  11. Heineke, J. and Molkentin, J. D. (2006) Regulation of cardiac hypertrophy by intracellular signalling pathways. Nat. Rev. Mol. Cell Biol. 7, 589-600. https://doi.org/10.1038/nrm1983
  12. Kedzierski, R. M. and Yanagisawa, M. (2011) Endothelin system: the double-edged sword in health and disease. Annu. Rev. Pharmacol. Toxicol. 41, 851-876.
  13. Kelly, R. A., Eid, H., Kramer, B. K., O'Neill, M., Liang, B. T., Reers, M. and Smith, T. W. (1990) Endothelin enhances the contractile responsiveness of adult rat ventricular myocytes to calcium by a pertussis toxin-sensitive pathway. J. Clin. Invest. 86, 1164-1171. https://doi.org/10.1172/JCI114822
  14. Kelso, E. J., McDermott, B. J., Silke, B. and Spiers, J. P. (2000) Endothelin(A) receptor subtype mediates endothelin-induced contractility in left ventricular cardiomyocytes isolated from rabbit myocardium. J. Pharmacol. Exp. Ther. 294, 1047-1052.
  15. Kobayashi, T., Miyauchi, T., Sakai, S., Kobayashi, M., Yamaguchi, I., Goto, K. and Sugishita, Y. (1999) Expression of endothelin-1, ETA and ETB receptors, and ECE and distribution of endothelin-1 in failing rat heart. Am. J. Physiol. 276, H1197-1206.
  16. Kohmoto, O., Ikenouchi, H., Hirata, Y., Momomura, S., Serizawa, T. and Barry, W. H. (1993) Variable effects of endothelin-1 on [$Ca^{2+}$]i transients, pHi, and contraction in ventricular myocytes. Am. J. Physiol. 265, H793-800.
  17. Li, K., Stewart, D. J. and Rouleau, J. L. (1991) Myocardial contractile actions of endothelin-1 in rat and rabbit papillary muscles. Role of endocardial endothelium. Circ. Res. 69, 301-312. https://doi.org/10.1161/01.RES.69.2.301
  18. Modesti, P. A., Vanni, S., Paniccia, R., Bandinelli, B., Bertolozzi, I., Polidori, G., Sani, G. and Neri Serneri, G. G. (1999) Characterization of endothelin-1 receptor subtypes in isolated human cardiomyocytes. J. Cardiovasc. Pharmacol. 34, 333-339. https://doi.org/10.1097/00005344-199909000-00003
  19. Moe, G. W., Albernaz, A., Naik, G. O., Kirchengast, M. and Stewart, D. J. (1998) Benefi cial effects of long-term selective endothelin type A receptor blockade in canine experimental heart failure. Cardiovasc. Res. 39, 571-579. https://doi.org/10.1016/S0008-6363(98)00169-2
  20. Mulder, P., Richard, V., Derumeaux, G., Hogie, M., Henry, J. P., Lallemand, F., Compagnon, P., Macé, B., Comoy, E., Letac, B. and Thuillez, C. (1997) Role of endogenous endothelin in chronic heart failure: effect of long-term treatment with an endothelin antagonist on survival, hemodynamics, and cardiac remodeling. Circulation 96, 1976-1982. https://doi.org/10.1161/01.CIR.96.6.1976
  21. Napoli, C., Liguori, A., Sorice, P., di Benedetto, A., Ciafre, S., Posca, T., di Ieso, N. and D'Armiento, F. P. (1996) Relations between vasoactive hormones and diastolic function in hypertensive uraemic patients. J. Intern. Med. 240, 389-394. https://doi.org/10.1046/j.1365-2796.1996.79878000.x
  22. Onishi, K., Ohno, M., Little, W. C. and Cheng, C. P. (1999) Endogenous endothelin-1 depresses left ventricular systolic and diastolic performance in congestive heart failure. J. Pharmacol. Exp. Ther. 288, 1214-1222.
  23. Pi, Y., Kemnitz, K. R., Zhang, D., Kranias, E. G. and Walker, J. W. (2002) Phosphorylation of troponin I controls cardiac twitch dynamics: evidence from phosphorylation site mutants expressed on a troponin I-null background in mice. Circ. Res. 90, 649-656. https://doi.org/10.1161/01.RES.0000014080.82861.5F
  24. Pi, Y., Sreekumar, R., Huang, X. and Walker, J. W. (1997) Positive inotropy mediated by diacylglycerol in rat ventricular myocytes. Circ. Res. 81, 92-100. https://doi.org/10.1161/01.RES.81.1.92
  25. Pieske, B., Beyermann, B., Breu, V., Löffl er, B. M., Schlotthauer, K., Maier, L. S., Schmidt-Schweda, S., Just, H. and Hasenfuss, G. (1999) Functional effects of endothelin and regulation of endothelin receptors in isolated human nonfailing and failing myocardium. Circulation 99, 1802-1809. https://doi.org/10.1161/01.CIR.99.14.1802
  26. Piuhola, J., Mäkinen, M., Szokodi, I. and Ruskoaho, H. (2003) Dual role of endothelin-1 via ETA and ETB receptors in regulation of cardiac contractile function in mice. Am. J. Physiol. Heart Circ. Physiol. 285, H112-118. https://doi.org/10.1152/ajpheart.00480.2002
  27. Ponicke, K., Vogelsang, M., Heinroth, M., Becker, K., Zolk, O., Böhm, M., Zerkowski, H. R. and Brodde, O. E. (1998) Endothelin receptors in the failing and nonfailing human heart. Circulation 97, 744-751. https://doi.org/10.1161/01.CIR.97.8.744
  28. Prendergast, B. D., Anning, P. B., Lewis, M. J. and Shah, A. M. (1997) Regulation of left ventricular relaxation in the isolated guinea-pig heart by endogenous endothelin. Cardiovasc. Res. 33, 131-138. https://doi.org/10.1016/S0008-6363(96)00174-5
  29. Rich, S. and McLaughlin, V. V. (2003) Endothelin receptor blockers in cardiovascular disease. Circulation 108, 2184-2190. https://doi.org/10.1161/01.CIR.0000094397.19932.78
  30. Saetrum Opgaard, O., Möller, S., de Vries, R., Edvinsson, L. and Saxena, P. R. (2000) Positive inotropic responses mediated by endothelin ET(A) and ET(B) receptors in human myocardial trabeculae. Clin. Sci. (Lond). 99, 161-168. https://doi.org/10.1042/CS19990302
  31. Stones, R., Gilbert, S. H., Benoist, D. and White, E. (2008) Inhomogeneity in the response to mechanical stimulation: cardiac muscle function and gene expression. Prog. Biophys. Mol. Biol. 97, 268- 281. https://doi.org/10.1016/j.pbiomolbio.2008.02.010
  32. Volkmann, R., Bokvist, K. and Wennmalm, A. (1990) Endothelin has no positive inotropic effect in guinea-pig atria or papillary muscle. Acta. Physiol. Scand. 138, 345-348. https://doi.org/10.1111/j.1748-1716.1990.tb08856.x
  33. Wang, J. X., Paik, G. and Morgan, J. P. (1991) Endothelin 1 enhances myofi lament $Ca^{2+}$ responsiveness in aequorin-loaded ferret myocardium. Circ. Res. 69, 582-589. https://doi.org/10.1161/01.RES.69.3.582
  34. Westfall, M. V., Lee, A. M. and Robinson, D. A. (2005) Differential contribution of troponin I phosphorylation sites to the endothelinmodulated contractile response. J. Biol. Chem. 280, 41324-41331. https://doi.org/10.1074/jbc.M506043200
  35. Yamamoto, K., Masuyama, T., Sakata, Y., Doi, R., Ono, K., Mano, T., Kondo, H., Kuzuya, T., Miwa, T. and Hori, M. (2000a) Local neurohumoral regulation in the transition to isolated diastolic heart failure in hypertensive heart disease: absence of AT1 receptor downregulation and 'overdrive' of the endothelin system. Cardiovasc. Res. 46, 421-432. https://doi.org/10.1016/S0008-6363(00)00024-9
  36. Yamamoto, K., Masuyama, T., Sakata, Y., Mano, T., Nishikawa, N., Kondo, H., Akehi, N., Kuzuya, T., Miwa, T. and Hori, M. (2000b) Roles of renin-angiotensin and endothelin systems in development of diastolic heart failure in hypertensive hearts. Cardiovasc. Res. 47, 274-283. https://doi.org/10.1016/S0008-6363(00)00101-2
  37. Yang, H. T., Sakurai, K., Sugawara, H., Watanabe, T., Norota, I. and Endoh, M. (1999) Role of $Na^{+}$/$Ca^{2+}$ exchange in endothelin-1-induced increases in $Ca^{2+}$ transient and contractility in rabbit ventricular myocytes: pharmacological analysis with KB-R7943. Br. J. Pharmacol. 126, 1785-1795. https://doi.org/10.1038/sj.bjp.0702454
  38. Zile, M. R., Baicu, C. F. and Gaasch, W. H. (2004) Diastolic heart failure-- abnormalities in active relaxation and passive stiffness of the left ventricle. N. Engl. J. Med. 350, 1953-1959. https://doi.org/10.1056/NEJMoa032566
  39. Zolk, O., Quattek, J., Sitzler, G., Schrader, T., Nickenig, G., Schnabel, P., Shimada, K., Takahashi, M. and Böhm, M. (1999) Expression of endothelin-1, endothelin-converting enzyme, and endothelin receptors in chronic heart failure. Circulation 99, 2118-2123. https://doi.org/10.1161/01.CIR.99.16.2118