TRAF Family Member 4 Promotes Cardiac Hypertrophy Through the Activation of the AKT Pathway

BACKGROUND: Pathological cardiac hypertrophy is a major cause of heart failure morbidity. The complex mechanism of intermolecular interactions underlying the pathogenesis of cardiac hypertrophy has led to a lack of development and application of therapeutic methods. METHODS AND RESULTS: Our study provides the first evidence that TRAF4, a member of the tumor necrosis factor receptor–associated factor (TRAF) family, acts as a promoter of cardiac hypertrophy. Here, Western blotting assays demonstrated that TRAF4 is upregulated in cardiac hypertrophy. Additionally, TRAF4 deletion inhibits the development of cardiac hypertrophy in a mouse model after transverse aortic constriction surgery, whereas its overexpression promotes phenylephrine stimulation‐induced cardiomyocyte hypertrophy in primary neonatal rat cardiomyocytes. Mechanistically, RNA‐seq analysis revealed that TRAF4 promoted the activation of the protein kinase B pathway during cardiac hypertrophy. Moreover, we found that inhibition of protein kinase B phosphorylation rescued the aggravated cardiomyocyte hypertrophic phenotypes caused by TRAF4 overexpression in phenylephrine‐treated neonatal rat cardiomyocytes, suggesting that TRAF4 may regulate cardiac hypertrophy in a protein kinase B–dependent manner. CONCLUSIONS: Our results revealed the regulatory function of TRAF4 in cardiac hypertrophy, which may provide new insights into developing therapeutic and preventive targets for this disease.