C‐C Motif Chemokine Receptor 9 Exacerbates Pressure Overload–Induced Cardiac Hypertrophy and Dysfunction

Background Maladaptive cardiac hypertrophy is a major risk factor for heart failure, which is the leading cause of death worldwide. C‐C motif chemokine receptor 9 ( CCR 9), a subfamily of the G protein–coupled receptor supergene family, has been highlighted as an immunologic regulator in the development and homing of immune cells and in immune‐related diseases. Recently, CCR 9 was found to be involved in the pathogenesis of other diseases such as cardiovascular diseases; however, the effects that CCR 9 exerts in cardiac hypertrophy remain elusive. Methods and Results We observed significantly increased CCR 9 protein levels in failing human hearts and in a mouse or cardiomyocyte hypertrophy model. In loss‐ and gain‐of‐function experiments, we found that pressure overload–induced hypertrophy was greatly attenuated by CCR 9 deficiency in cardiac‐specific CCR 9 knockout mice, whereas CCR 9 overexpression in cardiac‐specific transgenic mice strikingly enhanced cardiac hypertrophy. The prohypertrophic effects of CCR 9 were also tested in vitro, and a similar phenomenon was observed. Consequently, we identified a causal role for CCR 9 in pathological cardiac hypertrophy. Mechanistically, we revealed a lack of difference in the expression levels of mitogen‐activated protein kinases between groups, whereas the phosphorylation of AKT /protein kinase B and downstream effectors significantly decreased in CCR 9 knockout mice and increased in CCR 9 transgenic mice after aortic binding surgery. Conclusions The prohypertrophic effects of CCR 9 were not attributable to the mitogen‐activated protein kinase signaling pathway but rather to the AKT –mammalian target of rapamycin–glycogen synthase kinase 3β signaling cascade.