Ĭardiac hypertrophic stimuli lead to excessive activation of intricate but coordinated signaling pathways, such as the mitogen-activated protein kinase (MAPK), protein kinase C, phosphoinositide-3-kinase–protein kinase B/Akt (PI3K-PKB/Akt), and calcineurin/nuclear factor of activated T cell pathways. The complex process of cardiac hypertrophy involves abnormal protein synthesis, excessive activation of multiple factors and pathways, accumulation of extracellular matrix, and fetal cardiac gene re-expression, leading to cardiac dysfunction and eventually heart failure. Cardiac hypertrophy, which is characterized by the enlargement of cardiomyocytes and interstitial fibrosis, is the primary response of the heart to mechanical stress induced by extrinsic factors, including increased pressure or volume overload in hypertension and valvular diseases, or intrinsic factors such as ischemia-induced cardiac remodeling and expansive cardiomyopathy. 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.Ĭardiovascular disease, which is the leading cause of death worldwide, has become a global challenge. Using a TAK1-specific inhibitor in rescue experiments confirmed that the activation of TAK1 is essential for GCN5-mediated cardiac hypertrophy. 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. Similar results were obtained upon stimulation of NRCMs (having GCN5 overexpressed or knocked down) with phenylephrine.

In contrast, inhibition of GCN5 impairs the development of pathological cardiac hypertrophy. GCN5 overexpression aggravated the cardiac hypertrophy triggered by transverse aortic constriction surgery. GCN5 expression was increased in isolated neonatal rat cardiomyocytes (NRCMs) and mouse hearts of a hypertrophic mouse model. This study aimed to explore the role of GCN5 in the development of pathological cardiac hypertrophy. However, the function of GCN5 in pathological cardiac hypertrophy remains unclear. 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. 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.

Pathological hypertrophy