APJ acts as a dual receptor in cardiac hypertrophy

作者：Scimia Maria Cecilia; Hurtado Cecilia; Ray Saugata; Metzler Scott; Wei Ke; Wang Jianming; Woods Chris E; Purcell Nicole H; Catalucci Daniele; Akasaka Takeshi; Bueno Orlando F; Vlasuk George P; Kaliman Perla; Bodmer Rolf; Smith Layton H; Ashley Euan; Mercola Mark; Brown Joan Heller; Ruiz Lozano Pilar^*

来源：Nature, 2012, 488(7411): 394-398.

DOI：10.1038/nature11263

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.

• 出版日期2012-8-16