OTUD7a Accelerates Pathological Cardiac Hypertrophy via TAK1 Activation

BACKGROUND: Cardiac hypertrophy is one of the major causes of heart failure and sudden cardiac death. OTUD7a (OTU domain–containing protein 7a) is identified as a deubiquitinizing enzyme and a possible tumor suppressor. The present study is aimed at exploring the potential role and key downstream effectors of OTUD7a in cardiac hypertrophy. METHODS: The expression level of OTUD7a was detected in the cardiomyocytes with phenylephrine stimuli and the hearts subjected to transverse aortic constriction surgery. Then, the potential effects of OTUD7a on cardiac hypertrophy were evaluated in vivo by using cardiac-specific OTUD7a knockout mice and adeno-associated virus serotype 9-OTUD7a–infected mice. To further explore the direct modulation of OTUD7a on cardiomyocytes, hypertrophic parameters were detected in phenylephrine-stimulated cardiomyocytes with adenovirus system–induced OTUD7a overexpression or depletion. Furthermore, RNA-sequencing and interactome analysis, which were followed by multiple molecular biological methodologies, were combined to identify the direct target and corresponding molecular events contributing to OTUD7a function. RESULTS: Cardiac hypertrophy stimulates expression of OTUD7a in vitro and in vivo. Our data clearly showed that OTUD7a deficiency alleviates pathological cardiac hypertrophy in the transverse aortic constriction mouse model as well as in phenylephrine-treated cardiomyocytes, whereas overexpression of OTUD7a aggravated hypertrophic heart in vivo and enhanced cardiomyocyte enlargement in vitro. Mechanistically, TAK1 (transforming growth factor-β–activated kinase 1) was identified as a direct and essential target of OTUD7a in cardiac hypertrophy. To be more specific, OTUD7a directly interacts with TAK1 to inhibit the ubiquitination degradation of TAK1 and subsequently increase the phosphorylation levels of TAK1 and its downstream JNK (c-Jun N-terminal kinase)/P38. 5Z-7-oxozeaenol, a TAK1 inhibitor, blocked the detrimental effects of OTUD7a. Moreover, overexpression of TAK1 abolished the protection of OTUD7a depletion. CONCLUSIONS: Our findings, for the first time, provide evidence supporting OTUD7a as a novel promoter of pathological cardiac hypertrophy and indicate that targeting the OTUD7a-TAK1 axis represents a promising therapeutic strategy for cardiac hypertrophy and related heart failure.