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 (ccr9),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,ccr9 was found to be involved in the pathogenesis of other diseases such as cardiovascular diseases; however,the effects that ccr9 exerts in cardiac hypertrophy remain elusive. methods and results: we observed significantly increased ccr9 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 ccr9 deficiency in cardiac-specific ccr9 knockout mice,whereas ccr9 overexpression in cardiac-specific transgenic mice strikingly enhanced cardiac hypertrophy. the prohypertrophic effects of ccr9 were also tested in vitro,and a similar phenomenon was observed. consequently,we identified a causal role for ccr9 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 ccr9 knockout mice and increased in ccr9 transgenic mice after aortic binding surgery. conclusions: the prohypertrophic effects of ccr9 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. © 2016 the authors. published on behalf of the american heart association,inc.,by wiley blackwell.