Skip to main content

Ischemic heart failure enhances endogenous myocardial apelin and APJ receptor expression

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.

Abbreviations

CHO:

Chinese hamster ovary

DTT:

dithiothreitol

EDTA:

ethylenediaminotetraacetic acid

EIA:

enzyme immunoassay

LAD:

left anterior descending

SDS:

sodium dodecyl sulphate

References

  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.

    PubMed  Article  CAS  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.

    PubMed  Article  CAS  Google Scholar 

  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.

    PubMed  Article  CAS  Google Scholar 

  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.

    PubMed  Article  CAS  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.

    PubMed  Article  CAS  Google Scholar 

  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.

    PubMed  Article  CAS  Google Scholar 

  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.

    PubMed  Article  CAS  Google Scholar 

  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.

    PubMed  Article  CAS  Google Scholar 

  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.

    PubMed  Article  CAS  Google Scholar 

  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.

    PubMed  Article  CAS  Google Scholar 

  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.

    PubMed  Article  CAS  Google Scholar 

  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.

    PubMed  Article  CAS  Google Scholar 

  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.

    PubMed  Article  CAS  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    PubMed  Google Scholar 

  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.

    PubMed  Article  CAS  Google Scholar 

  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.

    PubMed  Article  CAS  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.

    PubMed  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  Article  CAS  Google Scholar 

  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.

    PubMed  Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Y. Joseph Woo.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Atluri, P., Morine, K.J., Liao, G.P. et al. Ischemic heart failure enhances endogenous myocardial apelin and APJ receptor expression. Cell Mol Biol Lett 12, 127–138 (2007). https://doi.org/10.2478/s11658-006-0058-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2478/s11658-006-0058-7

Key words

  • Apelin
  • G protein coupled receptor
  • APJ
  • Inotrope