Ubiquitin-Specifc Protease 4 And 18 In Pathological Cardiac Hypertrophy:Their Roles And Underlying Mechanisms

Aims: We aimed to investigate the roles of ubiquitin-specifc protease 4(USP4)and 18(USP18)in cardiac hypertrophy.Methods and Results: USP4 levels were consistently decreased in human failing hearts and in murine hypertrophied hearts,while USP18 levels were increased.Adenovirus-mediated gain-and loss-of function approaches indicated that USP4 and USP18 attenuated myocyte hypertrophy induced by Ang II in vitro.To corroborate the anti-hypertrophic roles of USP4 and USP18 in vivo,we generated USP4 and USP18 global knockout mice and mice with cardiac-specific overexpression of USP4 or USP18.Consistent with the in vitro study,USP4 or USP18 depletion exacerbated the hypertrophic phenotype and cardiac dysfunction in mice subjected to pressure overload,whereas overexpression of USP4 or USP18 ameliorated the development of pathological cardiac hypertrophy compared to their control littermates.Molecular analysis revealed that USP4 and USP18 exerted suppressive effect on the activation of TAK1-JNK1/2-P38 MAPK signaling in hypertrophied hearts,and blockage of TAK1 activation abolished the pathological effects of USP4 or USP18 depletion in vivo.Conclusion: These findings provide the first evidence for the involvement of USP4 and USP18 in cardiac hypertrophy,and shed light on the therapeutic potential of targeting the USP family in the treatment of cardiac hypertrophy.