Journal
NATURE
Volume 488, Issue 7411, Pages 394-398Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nature11263
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Funding
- Wyeth Sponsored Research Agreement
- National Institutes of Health (NIH) [R01HL086879, R37HL059502, R01HL083463, R01HL054732, NS05422, RO1HL28143, P01 HL085577]
- Sanford Children's Center
- Ellison Medical Foundation
- Muscular Dystrophy association
- Florida Department of Health [06-NIR-09]
- California Institute for Regenerative Medicine
- Italian Ministry of Research and Education
- Italian Society of Cardiology (SIC and Sanofi-Aventis Foundation)
- American Heart Association Postdoctoral Award
- Ministerio de Ciencia e Innovacion (MICINN) Spain [SAF2010-15050]
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Cardiac hypertrophy is initiated as an adaptive response to sustained overload but progresses pathologically as heart failure ensues(1). 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 G alpha(i) 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 beta-arrestins or by pharmacological doses of apelin acting through G alpha(i). 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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