FIGURE 7.

Diverse APJ signaling pathways activated by prolonged mechanical load or apelin. APJ translates apelin and stretch stimuli into distinct downstream signaling pathways. Apelin stimulation induces G_αi-dependent signaling to promote physiological hypertrophy and prosurvival signaling through the activation of Akt–mTOR and ERK1/2 (blue arrows). G_αi also inhibits deleterious cAMP–PKA pathway to serve a cardioprotective role (black dashed arrows). On the other hand, membrane stretch activates a β-arrestin-dependent program that results in pathological hypertrophy although the detailed downstream mechanisms are unresolved (red arrows). Importantly, there is a functional interplay between apelin- and stretch-dependent APJ signaling, in which apelin–APJ signaling blunts stretch-induced pathological signaling while stretch–APJ signaling interferes with apelin-induced G_αi activation. Although the apelin–APJ system involves G_αq-dependent signaling pathway (Figure 6), the relevance of this pathway to pathological hypertrophy has not been examined.