Circulation Research. 2002;91:434-440
Published online before print August 15, 2002, doi: 10.1161/01.RES.0000033522.37861.69
Published online before print August 15, 2002, doi: 10.1161/01.RES.0000033522.37861.69
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© 2002 American Heart Association, Inc.
Integrative Physiology |
Apelin, the Novel Endogenous Ligand of the Orphan Receptor APJ, Regulates Cardiac Contractility
From the Departments of Pharmacology and Toxicology (I.Sz., H.T., S.P., J.P., J.R., H.R.) and Physiology (P.T., S.V.-M, M.I.), Biocenter Oulu, University of Oulu, Oulu, Finland; and the Heart Institute (I.Sz.), Faculty of Medicine, University of Pécs, Pécs, Hungary; and the First Department of Internal Medicine (G.F., M.T.), Semmelweis University, Budapest, Hungary.
Correspondence to Heikki Ruskoaho, MD, PhD, Dept of Pharmacology and Toxicology, Faculty of Medicine, University of Oulu, PO Box 5000, 90014 University of Oulu, Finland. E-mail heikki.ruskoaho{at}oulu.fi
The orphan receptor APJ and its recently identified endogenous ligand, apelin, exhibit high levels of mRNA expression in the heart. However, the functional importance of apelin in the cardiovascular system is not known. In isolated perfused rat hearts, infusion of apelin (0.01 to 10 nmol/L) induced a dose-dependent positive inotropic effect (EC50: 33.1±1.5 pmol/L). Moreover, preload-induced increase in dP/dtmax was significantly augmented (P<0.05) in the presence of apelin. Inhibition of phospholipase C (PLC) with U-73122 and suppression of protein kinase C (PKC) with staurosporine and GF-109203X markedly attenuated the apelin-induced inotropic effect (P<0.001). In addition, zoniporide, a selective inhibitor of Na+-H+ exchange (NHE) isoform-1, and KB-R7943, a potent inhibitor of the reverse mode Na+-Ca2+ exchange (NCX), significantly suppressed the response to apelin (P<0.001). Perforated patch-clamp recordings showed that apelin did not modulate L-type Ca2+ current or voltage-activated K+ currents in isolated adult rat ventricular myocytes. Apelin mRNA was markedly downregulated in cultured neonatal rat ventricular myocytes subjected to mechanical stretch and in vivo in two models of chronic ventricular pressure overload. The present study provides the first evidence for the physiological significance of apelin in the heart. Our results show that apelin is one of the most potent endogenous positive inotropic substances yet identified and that the inotropic response to apelin may involve activation of PLC, PKC, and sarcolemmal NHE and NCX.
Key Words: apelin • contractility • signal transduction • gene expression
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|
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|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
 |
|
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|
|
|
|
 |
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
 |
|
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|
|
|
|
|
|
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|
|
|
|
|
|
J. P. Goetze and R. Videbaek More hormones spilt in heart failure: linking renal sympathetic activation to clinical outcome Eur. Heart J., May 1, 2005; 26(9): 861 - 862. [Full Text] [PDF]
|
|
|
|
|
|
J. Boucher, B. Masri, D. Daviaud, S. Gesta, C. Guigne, A. Mazzucotelli, I. Castan-Laurell, I. Tack, B. Knibiehler, C. Carpene, et al. Apelin, a Newly Identified Adipokine Up-Regulated by Insulin and Obesity Endocrinology, April 1, 2005; 146(4): 1764 - 1771. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-C. Zhong, D.-Y. Huang, G.-F. Liu, H.-Y. Jin, Y.-M. Yang, Y.-F. Li, X.-H. Song, and K. Du Effects of all-trans retinoic acid on orphan receptor APJ signaling in spontaneously hypertensive rats Cardiovasc Res, February 15, 2005; 65(3): 743 - 750. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. K. Lee, V. R. Saldivia, T. Nguyen, R. Cheng, S. R. George, and B. F. O'Dowd Modification of the Terminal Residue of Apelin-13 Antagonizes Its Hypotensive Action Endocrinology, January 1, 2005; 146(1): 231 - 236. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. A. Losano On the cardiovascular activity of apelin Cardiovasc Res, January 1, 2005; 65(1): 8 - 9. [Full Text] [PDF]
|
|
|
|
|
|
E. A. Ashley, J. Powers, M. Chen, R. Kundu, T. Finsterbach, A. Caffarelli, A. Deng, J. Eichhorn, R. Mahajan, R. Agrawal, et al. The endogenous peptide apelin potently improves cardiac contractility and reduces cardiac loading in vivo Cardiovasc Res, January 1, 2005; 65(1): 73 - 82. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. J. Pemberton, H. Tokola, Z. Bagi, A. Koller, J. Pontinen, A. Ola, O. Vuolteenaho, I. Szokodi, and H. Ruskoaho Ghrelin induces vasoconstriction in the rat coronary vasculature without altering cardiac peptide secretion Am J Physiol Heart Circ Physiol, October 1, 2004; 287(4): H1522 - H1529. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. F. Berry, T. J. Pirolli, V. Jayasankar, J. Burdick, K. J. Morine, T. J. Gardner, and Y. J. Woo Apelin Has In Vivo Inotropic Effects on Normal and Failing Hearts Circulation, September 14, 2004; 110(11_suppl_1): II-187 - II-193. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Ishida, T. Hashimoto, Y. Hashimoto, S. Nishiwaki, T. Iguchi, S. Harada, T. Sugaya, H. Matsuzaki, R. Yamamoto, N. Shiota, et al. Regulatory Roles for APJ, a Seven-transmembrane Receptor Related to Angiotensin-type 1 Receptor in Blood Pressure in Vivo J. Biol. Chem., June 18, 2004; 279(25): 26274 - 26279. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. Tenhunen, B. Sarman, R. Kerkela, I. Szokodi, L. Papp, M. Toth, and H. Ruskoaho Mitogen-activated Protein Kinases p38 and ERK 1/2 Mediate the Wall Stress-induced Activation of GATA-4 Binding in Adult Heart J. Biol. Chem., June 4, 2004; 279(23): 24852 - 24860. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. K. Lee, A. J. Lanca, R. Cheng, T. Nguyen, X. D. Ji, F. Gobeil Jr., S. Chemtob, Susan. R. George, and B. F. O'Dowd Agonist-independent Nuclear Localization of the Apelin, Angiotensin AT1, and Bradykinin B2 Receptors J. Biol. Chem., February 27, 2004; 279(9): 7901 - 7908. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. M. Chen, E. A. Ashley, D. X.F. Deng, A. Tsalenko, A. Deng, R. Tabibiazar, A. Ben-Dor, B. Fenster, E. Yang, J. Y. King, et al. Novel Role for the Potent Endogenous Inotrope Apelin in Human Cardiac Dysfunction Circulation, September 23, 2003; 108(12): 1432 - 1439. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Piuhola, M. Makinen, I. Szokodi, and H. Ruskoaho Dual role of endothelin-1 via ETA and ETB receptors in regulation of cardiac contractile function in mice Am J Physiol Heart Circ Physiol, June 5, 2003; 285(1): H112 - H118. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Avkiran and R. S Haworth Regulatory effects of G protein-coupled receptors on cardiac sarcolemmal Na+/H+ exchanger activity: signalling and significance Cardiovasc Res, March 15, 2003; 57(4): 942 - 952. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Piuhola, I. Szokodi, P. Kinnunen, M. Ilves, R. deChatel, O. Vuolteenaho, and H. Ruskoaho Endothelin-1 Contributes to the Frank-Starling Response in Hypertrophic Rat Hearts Hypertension, January 1, 2003; 41(1): 93 - 98. [Abstract] [Full Text] [PDF]
|
|