Targeting the Epigenetic Remodeler GCN5 Prevents Vascular Oxidative Stress and Endothelial Dysfunction in Obesity: Insights in Patients with Cardiometabolic Disease

Introduction: Epigenetic changes are important modulators of gene expression. The histone acetyltransferase gene non-derepressible 5 (Gcn5) is emerging as a pivotal epigenetic player in metabolism and cancer, yet its role in obesity and cardiovascular disease remains elusive. Aims: To investigate Gcn5 role in obesity-related endothelial dysfunction. Methods: Human aortic endothelial cells (HAECs) were exposed to vehicle or palmitic acid (200 uM) in the presence or in the absence of the Gcn5 pharmacological inhibitor CPTH2 or gene silencing. Ex-vivo inhibition of Gcn5 was performed in aortic rings from diet-induced obese and control mice. Chromatin immunoprecipitation (ChIP) was performed to investigate the epigenetic regulation of Nox2 promoter. In parallel, Gcn5/Nox2 expression was assessed by real-time PCR in vascular specimens isolated from obese patients and age-matched healthy controls. Endothelial-dependent vasodilation was also assessed in human vessels. Results: PA increased Gcn5 gene expression in HAECs. Gcn5 upregulation was associated with increased expression of the pro-oxidant enzyme Nox2. Interestingly, either Gcn5 inhibition or gene silencing prevented PA-induced Nox2 upregulation and oxidative stress accumulation. ChiP assay showed increased Gcn5 occupancy and enhanced histone 3 acetylation of lysine 14 (H3K14ac) on Nox2 promoter. In aortic rings from obese mice, pharmacological inhibition of Gcn5 by CPTH2 rescued endothelial-dependent vasorelaxation as compared to vehicle. Finally, Gcn5 was increased in vessels from obese patients and correlated with Nox2 expression and endothelial dysfunction. Conclusions: Our findings shed light on the importance of epigenetic regulation in obesity and pinpoint Gcn5 as a therapeutic target to prevent endothelial dysfunction in cardiometabolic disease.