APJ acts as a dual receptor in cardiac hypertrophy.

Abstract

Cardiac hypertrophy is initiated as an adaptive response to sustained overload but progresses pathologically as heart failure ensues. 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.

• Authors: Maria Cecilia Scimia, Cecilia Hurtado, Saugata Ray, Scott Metzler, Ke Wei, Jianming Wang, Chris E Woods, Nicole H Purcell, Daniele Catalucci, Takeshi Akasaka, Orlando F Bueno, George P Vlasuk, Perla Kaliman, Rolf Bodmer, Layton H Smith, Euan Ashley, Mark Mercola, Joan Heller Brown, Pilar Ruiz-Lozano
• Journal: Nature (Nature) Vol. 488 Issue 7411 Pg. 394-8 (Aug 16 2012) ISSN: 1476-4687 [Electronic] England
• PMID: 22810587 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Adipokines
• Apelin
• Apelin Receptors
• Apln protein, mouse
• Aplnr protein, mouse
• Arrestins
• Intercellular Signaling Peptides and Proteins
• Receptors, G-Protein-Coupled
• beta-Arrestins
• GTP-Binding Protein alpha Subunits, Gi-Go

Topics

• Adipokines
• Animals
• Aorta (pathology)
• Apelin
• Apelin Receptors
• Arrestins (deficiency, genetics, metabolism)
• Blood Pressure
• Cardiomegaly (metabolism, pathology, physiopathology, prevention & control)
• Female
• GTP-Binding Protein alpha Subunits, Gi-Go (metabolism)
• Intercellular Signaling Peptides and Proteins (deficiency, genetics, metabolism, pharmacology)
• Male
• Mechanoreceptors (metabolism)
• Mechanotransduction, Cellular (drug effects, physiology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Myocytes, Cardiac (drug effects, pathology)
• Receptors, G-Protein-Coupled (agonists, deficiency, genetics, metabolism)
• Signal Transduction (drug effects)
• beta-Arrestins