Aims Accumulation of reactive oxygen species (ROS) promotes vascular disease in obesity, but the underlying molecular mechanisms remain poorly understood. The adaptor p66Shc is emerging as a key molecule responsible for ROS generation and vascular damage. This study investigates whether epigenetic regulation of p66Shc 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 p66Shc promoter. Reprogramming SUV39H1, JMJD2C, and SRC-1 in isolated endothelial cells as well as in aortas from obese mice (LepOb/Ob) suppressed p66Shc-derived ROS, restored nitric oxide levels, and rescued endothelial dysfunction. Consistently, in vivo editing of chromatin remodellers blunted obesity-related vascular p66Shc expression. We show that SUV39H1 is the upstream effector orchestrating JMJD2C/SRC-1 recruitment to p66Shc promoter. Indeed, SUV39H1 overexpression in obese mice erased H3K9-related changes on p66Shc promoter, while SUV39H1 genetic deletion in lean mice recapitulated obesity-induced H3K9 remodelling and p66Shc 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.

中文翻译：

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H3K9 编辑酶 SUV39H1、JMJD2C 和 SRC-1 之间的相互作用在肥胖中驱动 p66Shc 转录和血管氧化应激

目的 活性氧 (ROS) 的积累促进肥胖患者的血管疾病，但其潜在的分子机制仍知之甚少。适配器 p66Shc 正在成为负责 ROS 生成和血管损伤的关键分子。这项研究调查了 p66Shc 的表观遗传调控是否会导致肥胖相关的血管疾病。方法和结果 与正常体重对照相比，在从肥胖受试者分离的内脏脂肪动脉 (VFA) 中观察到 ROS 驱动的内皮功能障碍。VFA 染色质修饰酶的基因分析显示甲基转移酶 SUV39H1（倍数变化，-6.9，P < 0.01）、去甲基化酶 JMJD2C（倍数变化，3.2，P < 0.01）和乙酰转移酶 SRC-1（倍数变化， 5.8，P < 0.01）肥胖与对照 VFA。这些变化与 p66Shc 启动子上组蛋白 3 赖氨酸 9 (H3K9) 的二 (H3K9me2) 和三甲基化 (H3K9me3) 以及乙酰化 (H3K9ac) 减少有关。在分离的内皮细胞和肥胖小鼠的主动脉 (LepOb/Ob) 中重编程 SUV39H1、JMJD2C 和 SRC-1 可抑制 p66Shc 衍生的 ROS，恢复一氧化氮水平，并挽救内皮功能障碍。一致地，染色质重塑剂的体内编辑减弱了肥胖相关的血管 p66Shc 表达。我们表明 SUV39H1 是协调 JMJD2C/SRC-1 募集到 p66Shc 启动子的上游效应器。事实上，肥胖小鼠中的 SUV39H1 过表达消除了 p66Shc 启动子上 H3K9 相关的变化，而瘦小鼠中的 SUV39H1 基因缺失重现了肥胖诱导的 H3K9 重塑和 p66Shc 转录。结论这些结果揭示了肥胖症内皮功能障碍的新表观遗传机制。靶向 SUV39H1 可能会减弱氧化转录程序，从而预防肥胖个体的血管疾病。