Interplay among H3K9-editing enzymes SUV39H1, JMJD2C and SRC-1 drives p66Shc transcription and vascular oxidative stress in obesity. (25th October 2017)

• Record Type: Journal Article
• Authors: Costantino, Sarah; Paneni, Francesco; Virdis, Agostino; Hussain, Shafaat; Mohammed, Shafeeq Ahmed; Capretti, Giuliana; Akhmedov, Alexander; Dalgaard, Kevin; Chiandotto, Sergio; Pospisilik, J Andrew; Jenuwein, Thomas; Giorgio, Marco; Volpe, Massimo; Taddei, Stefano; Lüscher, Thomas F; Cosentino, Francesco
• Is Part Of: European heart journal. Volume 40:Number 4(2019)
• Page Start: 383
• Page End: 391
• Publication Date: 2017-10-25
• Subjects: Epigenetics -- Chromatin remodelling -- Vascular disease -- Oxidative stress -- Endothelial dysfunction -- Obesity; Cardiology -- Periodicals; Heart -- Diseases -- Periodicals; 616.12005
• DOI: 10.1093/eurheartj/ehx615
• Languages: English
• ISSNs: 0195-668X

Abstract

Abstract: Aims: Accumulation of reactive oxygen species (ROS) promotes vascular disease in obesity, but the underlying molecular mechanisms remain poorly understood. The adaptor p66 Shc is emerging as a key molecule responsible for ROS generation and vascular damage. This study investigates whether epigenetic regulation of p66 Shc contributes to obesity-related vascular disease. Methods and results: ROS-driven endothelial dysfunction was observed in visceral fat arteries (VFAs) isolated from obese subjects when compared with normal weight controls. Gene profiling of chromatin-modifying enzymes in VFA revealed a significant dysregulation of methyltransferase SUV39H1 (fold change, −6.9, P < 0.01), demethylase JMJD2C (fold change, 3.2, P < 0.01), and acetyltransferase SRC-1 (fold change, 5.8, P < 0.01) in obese vs. control VFA. These changes were associated with reduced di-(H3K9me2) and trimethylation (H3K9me3) as well as acetylation (H3K9ac) of histone 3 lysine 9 (H3K9) on p66 Shc promoter. Reprogramming SUV39H1, JMJD2C, and SRC-1 in isolated endothelial cells as well as in aortas from obese mice ( Lep Ob/Ob ) suppressed p66 Shc -derived ROS, restored nitric oxide levels, and rescued endothelial dysfunction. Consistently, in vivo editing of chromatin remodellers blunted obesity-related vascular p66 Shc expression. We show that SUV39H1 is the upstream effector orchestrating JMJD2C/SRC-1 recruitment to p66 Shc promoter. Indeed, SUV39H1 overexpression in obese mice erased H3K9-related changes on p66 Shc promoter, while SUV39H1 genetic deletion in lean mice recapitulated obesity-induced H3K9 remodelling and p66 Shc transcription. Conclusion: These results uncover a novel epigenetic mechanism underlying endothelial dysfunction in obesity. Targeting SUV39H1 may attenuate oxidative transcriptional programmes and thus prevent vascular disease in obese individuals.