The Vascular Biology Unit, Queensland Research Centre for Peripheral Vascular Disease, School of Medicine and Dentistry, James Cook University, James Cook Drive, Douglas, Townsville, QLD 4811, Australia.
Atherosclerosis. 2013 Jun;228(2):295-305. doi: 10.1016/j.atherosclerosis.2013.02.019. Epub 2013 Feb 26.
Previous studies have suggested that homocysteine (Hcy) has wide-ranging biological effects, including accelerating atherosclerosis, impairing post injury endothelial repair and function, deregulating lipid metabolism and inducing thrombosis. However, the biochemical basis by which hyperhomocysteinemia (HHcy) contributes to cardiovascular diseases (CVDs) remains largely unknown. Several case-control studies have reported an association between HHcy and the presence of abdominal aortic aneurysms (AAA) and there are supportive data from animal models. Genotypic data concerning the association between variants of genes involved in the methionine cycle and AAA are conflicting probably due to problems such as reverse causality and confounding. The multifactorial nature of AAA suggests the involvement of additional epigenetic factors in disease formation. Elevated Hcy levels have been previously linked to altered DNA methylation levels in various diseases. Folate or vitamin B12 based methods of lowering Hcy have had disappointingly limited effects in reducing CVD events. One possible reason for the limited efficacy of such therapy is that they have failed to reverse epigenetic changes induced by HHcy. It is possible that individuals with HHcy have an "Hcy memory effect" due to epigenetic alterations which continue to promote progression of cardiovascular complications even after Hcy levels are lowered. It is possible that deleterious effect of prior, extended exposure to elevated Hcy concentrations have long-lasting effects on target organs and genes, hence underestimating the benefit of Hcy lowering therapies in CVD patients. Therapies targeting the epigenetic machinery as well as lowering circulating Hcy concentrations may have a more efficacious effect in reducing the incidence of cardiovascular complications.
先前的研究表明，同型半胱氨酸（Hcy）具有广泛的生物学效应，包括加速动脉粥样硬化、损害损伤后内皮修复和功能、调节脂质代谢和诱导血栓形成。然而，高同型半胱氨酸血症（HHcy）导致心血管疾病（CVDs）的生化基础在很大程度上仍然未知。几项病例对照研究报告了 HHcy 与腹主动脉瘤（AAA）的存在之间存在关联，并且动物模型也有支持性数据。关于涉及蛋氨酸循环中基因变异与 AAA 之间关联的基因型数据存在冲突，这可能是由于反向因果关系和混杂等问题所致。AAA 的多因素性质表明，疾病形成中涉及其他表观遗传因素。先前的研究表明，Hcy 水平升高与各种疾病中 DNA 甲基化水平的改变有关。降低 Hcy 的叶酸或维生素 B12 方法在降低 CVD 事件方面效果令人失望。这种治疗效果有限的一个可能原因是，它们未能逆转 HHcy 诱导的表观遗传变化。HHcy 个体可能由于表观遗传改变而具有“Hcy 记忆效应”，即使 Hcy 水平降低后，仍继续促进心血管并发症的进展。先前长时间暴露于升高的 Hcy 浓度对靶器官和基因可能具有持久的有害影响，因此低估了 Hcy 降低疗法对 CVD 患者的益处。针对表观遗传机制以及降低循环 Hcy 浓度的治疗方法可能在降低心血管并发症的发生率方面具有更有效的效果。
