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BY-NC-ND 3.0 license Open Access Published by De Gruyter November 19, 2006

Ischemic heart failure enhances endogenous myocardial apelin and APJ receptor expression

  • Pavan Atluri EMAIL logo , Kevin Morine , George Liao , Corinna Panlilio , Mark Berry , Vivian Hsu , William Hiesinger , Jeffrey Cohen and Y. Joseph Woo

Abstract

Apelin interacts with the APJ receptor to enhance inotropy. In heart failure, apelin-APJ coupling may provide a means of enhancing myocardial function. The alterations in apelin and APJ receptor concentrations with ischemic cardiomyopathy are poorly understood. We investigated the compensatory changes in endogenous apelin and APJ levels in the setting of ischemic cardiomyopathy.

Male, Lewis rats underwent LAD ligation and progressed into heart failure over 6 weeks. Corresponding animals underwent sham thoracotomy as control. Six weeks after initial surgery, the animals underwent hemodynamic functional analysis in the presence of exogenous apelin-13 infusion and the hearts were explanted for western blot and enzyme immunoassay analysis.

Western blot analysis of myocardial APJ concentration demonstrated increased APJ receptor protein levels with heart failure (1890750±133500 vs. 901600±143120 intensity units, n=8, p=0.00001). Total apelin protein levels increased with ischemic heart failure as demonstrated by enzyme immunoassay (12.0±4.6 vs. 1.0±1.2 ng/ml, n=5, p=0.006) and western blot (1579400±477733 vs. 943000±157600 intensity units, n=10, p=0.008). Infusion of apelin-13 significantly enhanced myocardial function in sham and failing hearts. We conclude that total myocardial apelin and APJ receptor levels increase in compensation for ischemic cardiomyopathy.

[1] O’Dowd, B.F., Heiber M., Chan, A., Heng, H.H.Q., Tsui, L.C., Kennedy, J.L., Shi, X., Petronis, A., George, S.R. and Nguyen, T. A human gene that shows identity with the gene encoding the angiotensin receptor is located on chromosome 11. Gene 136 (1993) 355–360. http://dx.doi.org/10.1016/0378-1119(93)90495-O10.1016/0378-1119(93)90495-OSearch in Google Scholar

[2] Tatemoto, K., Hosoya, M., Habata, Y., Fujii, R., Kakegawa, T., Zou, M.X., Kawamata, Y., Fukusumi, S., Hinuma, S., Kitada, C., Kurokawa, T., Onda, H., and Fujino, M. Isolation and characterization of a novel endogenous peptide ligand for the human APJ receptor. Biochem. Biophys. Res. Commun. 251 (1998) 471–476. http://dx.doi.org/10.1006/bbrc.1998.948910.1006/bbrc.1998.9489Search in Google Scholar PubMed

[3] Habata, Y., Fujii, R., Hosoya, M., Fukusumi, S., Kawamata, Y., Hinuma, S., Kitada, C., Nishizawa, N., Murosaki, S., Kurokawa, T., Onda, H., Tatemoto, K. and Fujino, M. Apelin the natural ligand of the orphan receptor APJ, is abundantly secreted in the colostrums. Biochim. Biophys. Acta 1452 (1999) 25–35. http://dx.doi.org/10.1016/S0167-4889(99)00114-710.1016/S0167-4889(99)00114-7Search in Google Scholar PubMed

[4] Kawamata, Y., Habata, Y., Fukusumi, S., Hosoya, M., Fujii, R., Hinuma, S., Nishizawa, N., Kitada, C., Onda, H., Nishimura, O. and Fujino, M. Molecular properties of apelin: tissue distribution and receptor binding. Biochim. Biophys. Acta 1538 (2001) 162–171. http://dx.doi.org/10.1016/S0167-4889(00)00143-910.1016/S0167-4889(00)00143-9Search in Google Scholar

[5] Medhurst, A.D., Jennings, C.A., Robbins, M.J., Davis, R.P., Ellis, C., Winborn, K.Y., Lawrie, K.W.M., Hervieu, G., Riley, G., Bolaky, J.E., Herrity, N.C., Murdock, P. and Darker, J.G. Pharmacological and immunohistochemical characterization of the APJ receptor and its endogenous ligand apelin. J. Neurochem. 84 (2003) 1162–1172. http://dx.doi.org/10.1046/j.1471-4159.2003.01587.x10.1046/j.1471-4159.2003.01587.xSearch in Google Scholar PubMed

[6] Lee, D.K., Saldivia, V.R., Nguyen, T., Cheng, R., George, S.R., and O’Dowd, B.F. Modification of the terminal residue of apelin-13 antagonises its hypotensive action. Endocrinology 146 (2005) 231–236. http://dx.doi.org/10.1210/en.2004-035910.1210/en.2004-0359Search in Google Scholar PubMed

[7] Lee, D.K., Lanca, A.J., Cheng, R., Nguyen, T., Ji, X.D., Gobeil, F., Chemtob, S., George, S.R., and O’Dowd, B.F. Agonist-independent nuclear localization of the apelin, angiotenesin AT1, and bradykinin B2 receptors. J. Biol. Chem. 279 (2004) 7901–7908. http://dx.doi.org/10.1074/jbc.M30637720010.1074/jbc.M306377200Search in Google Scholar PubMed

[8] Hosoya, M., Kawamata, Y., Fukusumi, S., Fuji, R., Habata, Y., Hinuma, S., Kitada, C., Honda, S., Kurokawa, T., Onda, H., Nishimura, O. and Fujino, M. Molecular and functional characteristics of APJ — tissue distribution of mRNA and interaction with the endogenous ligand apelin. J. Biol. Chem. 275 (2000) 21061–21067. http://dx.doi.org/10.1074/jbc.M90841719910.1074/jbc.M908417199Search in Google Scholar PubMed

[9] Lee, D.K., Cheng. R., Nguyen, T., Fan, T., Kariyawasam, A.P., Liu, Y., Osmond, D.H., George, S.R., and O’Dowd, B.F. Characterization of apelin, the ligand for the APJ receptor. J. Neurochem. 74 (2000) 34–41. http://dx.doi.org/10.1046/j.1471-4159.2000.0740034.x10.1046/j.1471-4159.2000.0740034.xSearch in Google Scholar PubMed

[10] O’Carroll, A.M. and Lolait, S.J. Regulation of rat APJ receptor messenger ribonucleic acid expression in magnocellular neurons of the paraventricular and supraopric nuclei by osmotic stimuli. J. Neuroendocrinol. 15 (2003) 661–666. http://dx.doi.org/10.1046/j.1365-2826.2003.01044.x10.1046/j.1365-2826.2003.01044.xSearch in Google Scholar PubMed

[11] Sunter, D., Hewson, A.K. and Dickson, S.L. sIntracerebroventricular injection of apelin-13 reduces food intake in the rat. Neurosci. Lett. 353 (2003) 1–4s. http://dx.doi.org/10.1016/S0304-3940(03)00351-310.1016/S0304-3940(03)00351-3Search in Google Scholar PubMed

[12] Horiuchi, Y., Fujii, T., Kamimura, Y. and Kawashima, K. The endogenous, immunologically active peptide apelin inhibits lymphocytic cholinergic activity duringimmunological responses. J. Neuroimmunol. 144 (2003) 46–52. http://dx.doi.org/10.1016/j.jneuroim.2003.08.02910.1016/j.jneuroim.2003.08.029Search in Google Scholar PubMed

[13] Szokodi, I., Tavi, P., Voutilainen-Myllyla, S., Ilves, M., Tokola, H., Pikkarainen, S., Piuhola, J., Rysa, J., Toth, M. and Ruskaoho, H. Apelin, the novel endogenous ligand of the orphan receptor APJ, regulates cardiac contractility. Circ. Res. 91 (2002) 434–440. http://dx.doi.org/10.1161/01.RES.0000033522.37861.6910.1161/01.RES.0000033522.37861.69Search in Google Scholar PubMed

[14] Ashley, E.A., Powers, J., Chen, M., Kundu, R., Finsterbach, T., Caffarelli, A., Deng, A., Eichorn, J., Mahajan, R., Agrawal, R., Greve, J., Robbins, R., Patterson, A.J., Bernstein, D. and Quertermous, T. The endogenous peptide apelin potently improves cardiac contractility and reduces cardiac loading in ivo. Cardiovasc. Res. 65 (2004) 73–82. http://dx.doi.org/10.1016/j.cardiores.2004.08.01810.1016/j.cardiores.2004.08.018Search in Google Scholar PubMed PubMed Central

[15] Berry, M.F., Pirolli, T.J., Jayasankar, V., Burdick, J., Morine, K.J., Gardner, T.J. and Woo YJ. Apelin has in vivo inotropic effects on normal and failing hearts. Circulation 110 Suppl. II (2004) II187–II193. 10.1161/01.CIR.0000138382.57325.5cSearch in Google Scholar PubMed

[16] Chen, M.M., Ashley, E.A., Deng, D.X.F., Tsalenko, A., Deng, A., Tabibiazar, R., Ben-Dor, A., Fenster, B., Yang, E., King, J.Y., Fowler, M., Robbins, R., Johnson, F.L., Bruhn, L., McDonagh, T., Dargie, H., Yakhini, Z., Tsao, P.S. and Quertermous, T. Novel role for the potent endogenous inotrope apelin in human cardiac dysfunction. Circulation 108 (2003) 1432–1439. http://dx.doi.org/10.1161/01.CIR.0000091235.94914.7510.1161/01.CIR.0000091235.94914.75Search in Google Scholar PubMed

[17] Foldes, G., Horkay, F., Szokodi, I., Vuolteenaho, O., Iilves, M., Lindstedt, K.A., Mayranpaa, sM., Sarman, B., Seres, L., Skoumal, R., Lako-Futo, Z., deChatel, R., Ruskoaho, H. and Toth, M. Circulating and cardiac levels of apelin, the novel ligand of the orphan receptor APJ, in patients with heart failure. Biochem. Biophys. Res. Commun. 308 (2003) 480–485. http://dx.doi.org/10.1016/S0006-291X(03)01424-410.1016/S0006-291X(03)01424-4Search in Google Scholar

[18] Jayasankar, V., Woo, Y.J., Bish, L.T., Pirolli, T.J., Chatterjee, S., Berry, M.F., Burdick, J., Gardner, T.J. and Sweeney, H.L. Gene transfer of hepatocyte growth factor attenuates postinfarction heart failure. Circulation 108 Suppl. 1 (2003) II230–6. 10.1161/01.cir.0000087444.53354.66Search in Google Scholar PubMed

[19] Woo, Y.J., Grand, T.J., Berry, M.F., Atluri, P., Moise, M.A., Hsu, V., Cohen, J., Fisher, O., Pirolli, T., Burdick, J., Taylor, M., Zentko, S., Jayasankar, V., Gardner, T.J. and Sweeney, H.L. Stromal cell-derived factor and granulocyte monocyte colony stimulating factor form a combined neovasculogenic therapy for ischemic cardiomyopathy. J. Thoracic. Cardiovasc. Surg. 130 (2005) 321–329. http://dx.doi.org/10.1016/j.jtcvs.2004.11.04110.1016/j.jtcvs.2004.11.041Search in Google Scholar PubMed

[20] Liu, Y.H., Yang, X.P., Nass, O., Sabbah, H.B., Peterson, E. and Carretero, O.A. Chronic heart failure induced coronary artery ligation in Lewis inbred rats. Am. J. Physiol. 272 (1997) H722–H727. 10.1152/ajpheart.1997.272.2.H722Search in Google Scholar PubMed

[21] Cingolani, O.H., Yang, X.P., Liu, Y.H., Villanueva, M., Rhaleb, N.E. and Carretero, O.A. Reduction of cardiac fibrosis decreases systolic performance without affecting diastolic function in hypertensive rats. Hypertension 43 (2004) 1067–1073. http://dx.doi.org/10.1161/01.HYP.0000125013.22494.c510.1161/01.HYP.0000125013.22494.c5Search in Google Scholar PubMed PubMed Central

[22] Tatemoto, K., Takayama, K., Zou, M., Kumaki, I., Zhang, W., Kumano, K. and Fujimiya, M. The novel peptide apelin lowers blood pressure via a nitric oxide-dependent mechanism. Regul. Pept. 99 (2001) 87–92. http://dx.doi.org/10.1016/S0167-0115(01)00236-110.1016/S0167-0115(01)00236-1Search in Google Scholar

Published Online: 2006-11-19
Published in Print: 2007-3-1

© 2006 University of Wrocław, Poland

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License.

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