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APJ acts as a dual receptor in cardiac hypertrophy

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Abstract

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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Figure 1: APJ-KO mice are protected from hypertrophy after TAC.
Figure 2: APJ mediates a stretch response that can be modulated by apelin.
Figure 3: Stretch activation of APJ enhances β-arrestin while reducing G-protein signalling.
Figure 4: APJ activation through mechanical stretch elicits cardiac hypertrophy.

Change history

  • 15 August 2012

    The spelling of an author name (T.A.) was corrected.

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Acknowledgements

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.

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M.S.C. and C.H. designed, performed experiments, analysed data and prepared the manuscript. C.E.W., S.R., S.A.M., K.W., S.M., J.W., N.H.P., T.A. and P.K. designed and performed experiments, and analysed data. D.C., G.P.V., R.B., O.F.B., L.H.S., E.A. and J.H.B. designed experiments. M.M. designed experiments and prepared the manuscript. P.R.L. designed and supervised experiments, analysed data and prepared the manuscript.

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Correspondence to Pilar Ruiz-Lozano.

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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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