Sum Hashum, Brewer Alison C
School of Cardiovascular and Metabolic Medicine & Sciences, British Heart Foundation Centre of Research Excellence, King's College London, SE5 9NU London, UK.
Front Biosci (Landmark Ed). 2025 Jan 7;30(1):26082. doi: 10.31083/FBL26082.
Cardiovascular disease (CVD) is the most prevalent cause of mortality and morbidity in the Western world. A common underlying hallmark of CVD is the plaque-associated arterial thickening, termed atherosclerosis. Although the molecular mechanisms underlying the aetiology of atherosclerosis remain unknown, it is clear that both its development and progression are associated with significant changes in the pattern of DNA methylation within the vascular cell wall. The endothelium is the major regulator of vascular homeostasis, and endothelial cell dysfunction (ED) is considered an early marker for atherosclerosis. Thus, it is speculated that changes in DNA methylation within endothelial cells may, in part, be causal in ED, leading to atherosclerosis and CVD generally. This review will evaluate the extensive evidence that environmental risk factors, known to be associated with atherosclerosis, such as diabetes, metabolic disorder, smoking, hypertension and hypercholesterolaemia can affect the methylome of the endothelium and consequently act to alter gene transcription and function. Further, the potential mechanisms whereby such risk factors might impact upon the activities and/or specificities of the epigenetic writers and erasers which determine the methylome [the DNA methyl transferases (DNMTs) and Ten Eleven translocases (TETs)] are considered here. Notably, the TET proteins are members of the 2-oxoglutarate-dependent dioxygenase superfamily which require molecular oxygen (O) and α-ketoglutarate (α-KG) as substrates and iron-2 (Fe II) as a cofactor. This renders their activities subject to modulation by hypoxia, metabolic flux and cellular redox. The potential significance of this, with respect to the impact of modifiable risk factors upon the activities of the TETs and the methylome of the endothelium is discussed.
心血管疾病（CVD）是西方世界最常见的死亡和发病原因。CVD的一个共同潜在特征是与斑块相关的动脉增厚，即动脉粥样硬化。尽管动脉粥样硬化病因的分子机制尚不清楚，但很明显，其发生和发展都与血管细胞壁内DNA甲基化模式的显著变化有关。内皮是血管稳态的主要调节因子，内皮细胞功能障碍（ED）被认为是动脉粥样硬化的早期标志物。因此，推测内皮细胞内DNA甲基化的变化可能部分导致ED，进而通常导致动脉粥样硬化和CVD。本综述将评估大量证据，即已知与动脉粥样硬化相关的环境风险因素，如糖尿病、代谢紊乱、吸烟、高血压和高胆固醇血症，可影响内皮的甲基化组，从而改变基因转录和功能。此外，本文还考虑了这些风险因素可能影响决定甲基化组的表观遗传书写器和擦除器（DNA甲基转移酶（DNMTs）和十一碳烯移位酶（TETs））的活性和/或特异性的潜在机制。值得注意的是，TET蛋白是依赖于2-酮戊二酸的双加氧酶超家族的成员，该超家族需要分子氧（O）和α-酮戊二酸（α-KG）作为底物，铁-2（Fe II）作为辅因子。这使得它们的活性受到缺氧、代谢通量和细胞氧化还原的调节。本文讨论了这一点对于可改变的风险因素对TETs活性和内皮甲基化组的影响的潜在意义。
