Cardiac hypertrophy is initiated as an adaptive response to sustained overload but progresses pathologically as heart failure ensues1. Here we report that genetic loss of APJ, a G-protein-coupled receptor, confers resistance to chronic pressure overload by markedly reducing myocardial hypertrophy and heart failure. In contrast, mice lacking apelin (the endogenous APJ ligand) remain sensitive, suggesting an apelin-independent function of APJ. Freshly isolated APJ-null cardiomyocytes exhibit an attenuated response to stretch, indicating that APJ is a mechanosensor. Activation of APJ by stretch increases cardiomyocyte cell size and induces molecular markers of hypertrophy. Whereas apelin stimulates APJ to activate Gαi and elicits a protective response, stretch signals in an APJ-dependent, G-protein-independent fashion to induce hypertrophy. Stretch-mediated hypertrophy is prevented by knockdown of β-arrestins or by pharmacological doses of apelin acting through Gαi. Taken together, our data indicate that APJ is a bifunctional receptor for both mechanical stretch and the endogenous peptide apelin. By sensing the balance between these stimuli, APJ occupies a pivotal point linking sustained overload to cardiomyocyte hypertrophy.
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Apelin receptor homodimer-oligomers revealed by single-molecule imaging and novel G protein-dependent signaling
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Levy, D., Garrison, R. J., Savage, D. D., Kannel, W. B. & Castelli, W. P. Prognostic implications of echocardiographically determined left ventricular mass in the Framingham Heart Study. N. Engl. J. Med. 322, 1561–1566 (1990)
Knowlton, K. U. et al. The alpha 1A-adrenergic receptor subtype mediates biochemical, molecular, and morphologic features of cultured myocardial cell hypertrophy. J. Biol. Chem. 268, 15374–15380 (1993)
Rapacciuolo, A., Esposito, G., Prasad, S. V. & Rockman, H. A. G protein-coupled receptor signalling in in vivo cardiac overload. Acta Physiol. Scand. 173, 51–57 (2001)
Rockman, H. A., Koch, W. J. & Lefkowitz, R. J. Seven-transmembrane-spanning receptors and heart function. Nature 415, 206–212 (2002)
O’Dowd, B. F. et al. A human gene that shows identity with the gene encoding the angiotensin receptor is located on chromosome 11. Gene 136, 355–360 (1993)
Tatemoto, K. et al. Isolation and characterization of a novel endogenous peptide ligand for the human APJ receptor. Biochem. Biophys. Res. Commun. 251, 471–476 (1998)
Szokodi, I. et al. Apelin, the novel endogenous ligand of the orphan receptor APJ, regulates cardiac contractility. Circ. Res. 91, 434–440 (2002)
Ashley, E. A. et al. The endogenous peptide apelin potently improves cardiac contractility and reduces cardiac loading in vivo. Cardiovasc. Res. 65, 73–82 (2005)
Jia, Y. X. et al. Apelin protects myocardial injury induced by isoproterenol in rats. Regul. Pept. 133, 147–154 (2006)
Siddiquee, K. et al. Apelin protects against angiotensin II-induced cardiovascular fibrosis and decreases plasminogen activator inhibitor type-1 production. J. Hypertens. 29, 724–731 (2011)
Chun, H. J. et al. Apelin signaling antagonizes Ang II effects in mouse models of atherosclerosis. J. Clin. Invest. 118, 3343–3354 (2008)
Kuba, K. et al. Impaired heart contractility in apelin gene-deficient mice associated with aging and pressure overload. Circ. Res. 101, e32–e42 (2007)
Charo, D. N. et al. Endogenous regulation of cardiovascular function by apelin-APJ. Am. J. Physiol. Heart Circ. Physiol. 297, H1904–H1913 (2009)
Scott, I. C. et al. The G protein-coupled receptor Agtrl1b regulates early development of myocardial progenitors. Dev. Cell 12, 403–413 (2007)
Frank, D. et al. Gene expression pattern in biomechanically stretched cardiomyocytes: evidence for a stretch-specific gene program. Hypertension 51, 309–318 (2008)
Zou, Y. et al. Mechanical stress activates angiotensin II type 1 receptor without the involvement of angiotensin II. Nature Cell Biol. 6, 499–506 (2004)
Iribe, G. et al. Axial stretch of rat single ventricular cardiomyocytes causes an acute and transient increase in Ca2+ spark rate. Circ. Res. 104, 787–795 (2009)
Bollensdorff, C., Lookin, O. & Kohl, P. Assessment of contractility in intact ventricular cardiomyocytes using the dimensionless ‘Frank-Starling Gain’ index. Pflügers Arch. 462, 39–48 (2011)
Civelli, O. GPCR deorphanizations: the novel, the known and the unexpected transmitters. Trends Pharmacol. Sci. 26, 15–19 (2005)
Means, C. K., Miyamoto, S., Chun, J. & Brown, J. H. S1P1 receptor localization confers selectivity for Gi-mediated cAMP and contractile responses. J. Biol. Chem. 283, 11954–11963 (2008)
Masri, B., Morin, N., Pedebernade, L., Knibiehler, B. & Audigier, Y. The apelin receptor is coupled to Gi1 or Gi2 protein and is differentially desensitized by apelin fragments. J Biol Chem 281, 18317–18326 (2006)
Kostenis, E. Is Gα16 the optimal tool for fishing ligands of orphan G-protein-coupled receptors? Trends Pharmacol. Sci. 22, 560–564 (2001)
Knowlton, K. U. et al. Divergent pathways mediate the induction of ANF transgenes in neonatal and hypertrophic ventricular myocardium. J. Clin. Invest. 96, 1311–1318 (1995)
Rockman, H. A. et al. Molecular and physiological alterations in murine ventricular dysfunction. Proc. Natl Acad. Sci. USA 91, 2694–2698 (1994)
Sadoshima, J. & Izumo, S. Mechanical stretch rapidly activates multiple signal transduction pathways in cardiac myocytes: potential involvement of an autocrine/paracrine mechanism. EMBO J. 12, 1681–1692 (1993)
Sadoshima, J., Xu, Y., Slayter, H. S. & Izumo, S. Autocrine release of angiotensin II mediates stretch-induced hypertrophy of cardiac myocytes in vitro. Cell 75, 977–984 (1993)
Magga, J., Vuolteenaho, O., Marttila, M. & Ruskoaho, H. Endothelin-1 is involved in stretch-induced early activation of B-type natriuretic peptide gene expression in atrial but not in ventricular myocytes: acute effects of mixed ET(A)/ET(B) and AT1 receptor antagonists in vivo and in vitro. Circulation 96, 3053–3062 (1997)
We are thankful to N. Ling, S. Zhao and F. Abdel-Wahhab for technical assistance; E. Sergienko for help optimizing arrestin assay; E. Adamson for reading the manuscript; and M. Querol for graphics design. This work was supported by Wyeth Sponsored Research Agreement and National Institutes of Health (NIH) grant R01HL086879 to P.R.L.; NIH grants R37HL059502 and R01HL083463 and the Sanford Children’s Center to M.M.; NIH grant R01HL054732, grants from the Ellison Medical Foundation and the Muscular Dystrophy association to R.B., NIH grant (NS05422) and Florida Department of Health grant 06-NIR-09 to L.H.S., and NIH grants RO1HL28143, P01 HL085577 to J.H.B. M.C.S. has received support from the California Institute for Regenerative Medicine (clinical fellow), the Italian Ministry of Research and Education and the Italian Society of Cardiology (SIC and Sanofi-Aventis Foundation). C.H. holds an American Heart Association Postdoctoral Award, S.R. is a Sanford Children’s Health Research Center fellow. P.K. is supported by SAF2010-15050 Ministerio de Ciencia e Innovación (MICINN) Spain.
The authors declare no competing financial interests.
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Scimia, M., Hurtado, C., Ray, S. et al. APJ acts as a dual receptor in cardiac hypertrophy. Nature 488, 394–398 (2012). https://doi.org/10.1038/nature11263
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