Center for Molecular Cardiology, University of Zürich, Switzerland.
University Heart Center, Cardiology, University Hospital Zurich, Switzerland.
Atherosclerosis. 2019 Feb;281:150-158. doi: 10.1016/j.atherosclerosis.2018.09.029. Epub 2018 Sep 26.
Albeit a consistent body of evidence supports the notion that genes influence cardiometabolic features and outcomes, the "non-genetic regulation" of this process is gaining increasing attention. Plastic chemical changes of DNA/histone complexes - known as epigenetic changes - critically determine gene activity by rapidly modifying chromatin accessibility to transcription factors. In this review, we describe the emerging role of chromatin modifications as fine tuners of gene transcription in adipogenesis, insulin resistance, macrophage polarization, immuno-metabolism, endothelial dysfunction and metabolic cardiomyopathy. Epigenetic processing participates in the dynamic interplay among different organs in the cardiometabolic patient. DNA methylation and post-translational histone modifications in both visceral and subcutaneous adipose tissue enable the transcription of genes implicated in lipo- and adipogenesis, inflammation and insulin resistance. Along the same line, complex networks of chromatin modifying enzymes are responsible for impaired nitric oxide bioavailability and defective insulin signalling in the vasculature, thus leading to reduced capillary recruitment and insulin delivery in the liver, skeletal muscle and adipose tissue. Furthermore, changes in methylation status of IL-4, IFNγ and Forkhead box P3 (Foxp3) gene loci are crucial for the polarization of immune cells, thus leading to adipose tissue inflammation and atherosclerosis. Cell-specific epigenetic information could advance our understanding of cardiometabolic processes, thus leading to individualized risk assessment and personalized therapeutic approaches in patients with cardiometabolic disturbances. The development of new chromatin modifying drugs indicates that targeting epigenetic changes is a promising approach to reduce the burden of cardiovascular disease in this setting.
尽管大量证据支持基因影响心脏代谢特征和结果的观点，但这一过程的“非遗传调控”正受到越来越多的关注。DNA/组蛋白复合物的可塑性化学变化——称为表观遗传变化——通过快速改变染色质对转录因子的可及性，从而对基因活性起着至关重要的决定作用。在这篇综述中，我们描述了染色质修饰作为在脂肪生成、胰岛素抵抗、巨噬细胞极化、免疫代谢、内皮功能障碍和代谢性心肌病中精细调节基因转录的新兴作用。表观遗传加工参与了心脏代谢患者体内不同器官之间的动态相互作用。内脏和皮下脂肪组织中的 DNA 甲基化和翻译后组蛋白修饰使涉及脂肪生成、炎症和胰岛素抵抗的基因转录。沿着同样的思路，染色质修饰酶的复杂网络负责血管中一氧化氮生物利用度的受损和胰岛素信号的缺陷，从而导致肝脏、骨骼肌和脂肪组织中毛细血管募集和胰岛素传递减少。此外，IL-4、IFNγ 和叉头框 P3 (Foxp3) 基因座的甲基化状态变化对于免疫细胞的极化至关重要，从而导致脂肪组织炎症和动脉粥样硬化。细胞特异性表观遗传信息可以促进我们对心脏代谢过程的理解，从而导致心脏代谢紊乱患者的个体化风险评估和个性化治疗方法。新型染色质修饰药物的开发表明，靶向表观遗传变化是减少心血管疾病负担的一种很有前途的方法。
