The main finding of this study were: (1) NPY was up-regulated in CH; (2) NPY inactivation inhibited CH and improved cardiac function in CH rats; (3) miR-216b mimic and FoxO4 siRNA attenuated cardiac hypertrophy in vitro and FoxO4 is a direct target of miR-216b; (4) NPY mediated CH in vitro through NPY1R/miR-216b/FoxO4 pathway (Fig.8). Here, FOXO4 is linked to cardiac hypertrophy.