Masi Stefano, Ambrosini Samuele, Mohammed Shafeeq A, Sciarretta Sebastiano, Lüscher Thomas F, Paneni Francesco, Costantino Sarah
Dipartimento di Medicina Clinica e Sperimentale, Università di Pisa, Pisa, Italy.
Center for Molecular Cardiology, University of Zürich, Zurich, Switzerland.
Antioxid Redox Signal. 2021 May 20;34(15):1165-1199. doi: 10.1089/ars.2020.8040. Epub 2020 Sep 9.
The prevalence of obesity and cardiometabolic phenotypes is alarmingly increasing across the globe and is associated with atherosclerotic vascular complications and high mortality. In spite of multifactorial interventions, vascular residual risk remains high in this patient population, suggesting the need for breakthrough therapies. The mechanisms underpinning obesity-related vascular disease remain elusive and represent an intense area of investigation. Epigenetic modifications-defined as environmentally induced chemical changes of DNA and histones that do not affect DNA sequence-are emerging as a potent modulator of gene transcription in the vasculature and might significantly contribute to the development of obesity-induced endothelial dysfunction. DNA methylation and histone post-translational modifications cooperate to build complex epigenetic signals, altering transcriptional networks that are implicated in redox homeostasis, mitochondrial function, vascular inflammation, and perivascular fat homeostasis in patients with cardiometabolic disturbances. Deciphering the epigenetic landscape in the vasculature is extremely challenging due to the complexity of epigenetic signals and their function in regulating transcription. An overview of the most important epigenetic pathways is required to identify potential molecular targets to treat or prevent obesity-related endothelial dysfunction and atherosclerotic disease. This would enable the employment of precision medicine approaches in this setting. Current and future research efforts in this field entail a better definition of the vascular epigenome in obese patients as well as the unveiling of novel, cell-specific chromatin-modifying drugs that are able to erase specific epigenetic signals that are responsible for maladaptive transcriptional alterations and vascular dysfunction in obese patients. . 34, 1165-1199.
全球范围内，肥胖和心血管代谢表型的患病率正以惊人的速度上升，且与动脉粥样硬化性血管并发症及高死亡率相关。尽管采取了多因素干预措施，但该患者群体的血管残余风险仍然很高，这表明需要突破性疗法。肥胖相关血管疾病的潜在机制仍不清楚，是一个深入研究的领域。表观遗传修饰（定义为不影响DNA序列的由环境诱导的DNA和组蛋白化学变化）正成为血管中基因转录的有力调节因子，并可能对肥胖诱导的内皮功能障碍的发展有显著影响。DNA甲基化和组蛋白翻译后修饰共同构建复杂的表观遗传信号，改变与心血管代谢紊乱患者的氧化还原稳态、线粒体功能、血管炎症和血管周围脂肪稳态相关的转录网络。由于表观遗传信号的复杂性及其在调节转录中的功能，解析血管中的表观遗传格局极具挑战性。需要对最重要的表观遗传途径进行概述，以确定治疗或预防肥胖相关内皮功能障碍和动脉粥样硬化疾病的潜在分子靶点。这将有助于在这种情况下采用精准医学方法。该领域当前和未来的研究工作需要更好地定义肥胖患者的血管表观基因组，以及揭示能够消除导致肥胖患者适应性不良转录改变和血管功能障碍的特定表观遗传信号的新型细胞特异性染色质修饰药物。. 34, 1165 - 1199。
