OTUD7a Is a Key detrimental factor of Pathological Cardiac Hypertrophy via activating TAK1

Objective: Cardiac hypertrophy is one of the major causes of heart failure and sudden cardiac death, OTU domain containing protein 7a (OTUD7a) 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 (PE) stimuli and the hearts subjected to transverse aortic constriction (TAC) 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 infecting mice. To further explore the direct modulation of OTUD7a on cardiomyocytes, hypertrophic parameters were detected in PE stimulated cardiomyocytes with adenovirus system induced OTUD7a overexpression or depletion. Furthermore, RNAsequencing and interactome analysis that was 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 pathologic cardiac hypertrophy in the TAC mouse model as well as in PE treated cardiomyocytes, whereas overexpression OTUD7a aggravated hypertrophic heart in vivo and enhanced cardiomyocyte enlargement in vitro. Mechanistically, TAK1 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 P38.