Pathological cardiac hypertrophy is a process of abnormal remodeling of cardiomyocytes in response to pressure overload or other stress stimuli, resulting in myocardial injury, which is a major risk factor for heart failure, leading to increased morbidity and mortality. General control nonrepressed protein 5 (GCN5)/lysine acetyltransferase 2 A, a member of the histone acetyltransferase and lysine acetyltransferase families, regulates a variety of physiological and pathological events. However, the function of GCN5 in pathological cardiac hypertrophy remains unclear. This study aimed to explore the role of GCN5 in the development of pathological cardiac hypertrophy. GCN5 expression was increased in isolated neonatal rat cardiomyocytes (NRCMs) and mouse hearts of a hypertrophic mouse model. GCN5 overexpression aggravated the cardiac hypertrophy triggered by transverse aortic constriction surgery. In contrast, inhibition of GCN5 impairs the development of pathological cardiac hypertrophy. Similar results were obtained upon stimulation of NRCMs (having GCN5 overexpressed or knocked down) with phenylephrine. Mechanistically, our results indicate that GCN5 exacerbates cardiac hypertrophy via excessive activation of the transforming growth factor β-activated kinase 1 (TAK1)-c-Jun N-terminal kinase (JNK)/p38 signaling pathway. Using a TAK1-specific inhibitor in rescue experiments confirmed that the activation of TAK1 is essential for GCN5-mediated cardiac hypertrophy. In summary, the current study elucidated the role of GCN5 in promotion of cardiac hypertrophy, thereby implying it to be a potential target for treatment.

• Trim55 knockout improved cardiac dysfunction and cardiomyocyte apoptosis after MI, whereas overexpression aggravated cardiac dysfunction after MI. • Trim55 regulated cardiomyocyte apoptosis by inhibiting the Nrf2/HO-1 pathway. • Trim55 regulated the Nrf2/HO-1 pathway by interacting with Nrf2. • Trim55 was regulated by the transcription factor Foxo3 under hypoxia.

Diabetic cardiomyopathy (DCM) is one of the most significant cardiovascular complications in patients with diabetes. Ubiquitin conjugating enzyme 9 (UBC9) is the only SUMO-E2 enzyme that plays a key role in cardiomyocytes homeostasis. This study aimed to elucidate the roles and mechanisms of UBC9 in DCM development. We established cardiomyocyte-specific UBC9 knockout mice and UBC9-overexpressing mice in vivo. A DCM model was established by feeding a high-fat diet and administering a low-dose streptozotocin injection. Proteomics, H&E staining, Sirius Red staining, WGA staining, real-time PCR, and western blotting were performed to examine fibrosis, hypertrophy, and mitophagy in the myocardium. Neonatal mouse cardiomyocytes (NMCMs) were cultured in vitro and stimulated with palmitic acid, UBC9 overexpression adenovirus, and small interfering RNA to establish UBC9 overexpression or knockdown NMCMs. Real-time PCR, western blotting, and immunoprecipitation were employed to examine the roles and mechanisms of UBC9 in cardiomyocyte mitophagy. The transcription and protein levels of UBC9 were significantly decreased in the myocardium of DCM mice. Cardiomyocyte-specific UBC9 knockout aggravated cardiac dysfunction, myocardial fibrosis, hypertrophy, and impaired mitophagy. Conversely, UBC9 overexpression produced opposite effects. UBC9 protected cardiomyocyte mitophagy independently of SUMOylation. UBC9 exerted protective effects against defective cardiomyocyte mitophagy by directly binding to NEDD4, enhancing RUNX2 ubiquitination and degradation, which in turn increased PSEN2 expression. Moreover, the impact of UBC9 on cardiomyocyte mitophagy was reversed upon PSEN2 knockdown. UBC9 alleviated DCM development through the NEDD4/RUNX2/PSEN2 pathway. These findings offer novel insights into the potential of UBC9 as a therapeutic target for DCM.