The Stretching Point

Science Signaling  21 Aug 2012:
Vol. 5, Issue 238, pp. ec219
DOI: 10.1126/scisignal.2003519

Binding of the adipokine apelin to the heterotrimeric GTP-binding protein (G protein)–coupled receptor (GPCR) APJ activates Gαi and protects against cardiac hypertrophy, a response that can lead to heart failure when induced by pressure overload. Scimia et al. found that fewer APJ knockout mice developed hypertrophy after transaortic constriction (an experimental procedure that induces pressure overload) than did wild-type or apelin knockout mice. Isolated cardiomyocytes from wild-type mice, but not those from APJ knockout mice, responded to stretch, which was decreased by the addition of apelin. The authors used human embryonic kidney cells stably expressing human APJ to analyze the downstream signaling pathways activated by stretch and apelin. In these cells, activation of ERK (extracellular signal–regulated kinase) was increased by apelin or stretch, and the Gαi inhibitor PTX blocked activation of ERK induced by apelin, but not stretch. Furthermore, apelin, but not stretch, attenuated the increase in adenosine 3',5'-monophosphate (cAMP) that was induced by isoproterenol (a β-adrenergic receptor agonist that triggers cardiac hypertrophy). In addition, apelin, but not stretch, stimulated the accumulation of inositol phosphate 1 (which is mediated by Gα16-induced activation of phospholipase C), although stretch decreased the apelin-induced accumulation of inositol phosphate 1. These results suggested that APJ transduced stretch through G protein–independent pathways. Indeed, stretch increased the recruitment of β-arrestin to APJ, both basally and in the presence of apelin. Application of stretch triggered hypertrophy in cardiomyocytes infected with an adenovirus expressing APJ, a response that was antagonized by apelin in a Gαi-dependent manner and that was prevented by siRNAs directed against β-arrestin1 or β-arrestin2. Thus, APJ can mediate both stretch-induced hypertrophy and apelin-induced cardioprotective responses.

M. C. Scimia, C. Hurtado, S. Ray, S. Metzler, K. Wei, J. Wang, C. E. Woods, N. H. Purcell, D. Catalucci, T. Akasaka, O. F. Bueno, G. P. Vlasuk, P. Kaliman, R. Bodmer, L. H. Smith, E. Ashley, M. Mercola, J. H. Brown, P. Ruiz-Lozano, APJ acts as a dual receptor in cardiac hypertrophy. Nature 488, 394–398 (2012). [PubMed]