Toghill Bradley J, Saratzis Athanasios, Harrison Seamus C, Verissimo Ana R, Mallon Eamonn B, Bown Matthew J
University of Leicester, Department of Cardiovascular Sciences and the NIHR Leicester Cardiovascular Biomedical Research Unit, Leicester, UK.
University of Leicester, Department of Cardiovascular Sciences and the NIHR Leicester Cardiovascular Biomedical Research Unit, Leicester, UK.
Atherosclerosis. 2015 Jul;241(1):121-9. doi: 10.1016/j.atherosclerosis.2015.05.001. Epub 2015 May 7.
Abdominal aortic aneurysm (AAA) is characterised by the chronic degradation and gradual, irreversible dilation of the abdominal aorta. Smoking, genetics, male sex and increased age are major factors associated with developing AAA. Rupture contributes to around 2% of deaths in all Caucasians over 65, and there is no pharmaco-therapeutic treatment. Methylation is an epigenetic modification to DNA, where a methyl group is added to a cytosine base 5' to a guanine (CpG dinucleotide). Methylation patterns are long term, inherited signatures that can induce changes in gene transcription, and can be affected by both genetic and environmental factors. Methylation changes are involved in hypertension and atherosclerosis, both of which are risk factors of, and often coexist with AAA. Extra-cellular matrix degradation and inflammation, both important pathological hallmarks of AAA, are also promoted by changes in CpG methylation in other diseases. Additionally, the adverse effects of smoking and ageing take place largely through epigenetic manipulation of the genome. Every factor associated with AAA appears to be associated with DNA methylation, yet no direct evidence confirms this. Future work to identify a link between global methylation and AAA, and differentially methylated regions may reveal valuable insight. The identification of a common epigenetic switching process may also signify a promising future for AAA pharmaco-therapeutic strategies. Epigenetic therapies are being designed to target pathogenic CpG methylation changes in other diseases, and it is feasible that these therapies may also be applicable to AAA in the future.
腹主动脉瘤（AAA）的特征是腹主动脉发生慢性退化并逐渐出现不可逆的扩张。吸烟、遗传因素、男性性别以及年龄增长是与腹主动脉瘤发病相关的主要因素。在65岁以上的所有白种人中，腹主动脉瘤破裂导致的死亡约占2%，并且目前尚无药物治疗方法。甲基化是一种DNA的表观遗传修饰，即在鸟嘌呤（CpG二核苷酸）5'端的胞嘧啶碱基上添加一个甲基基团。甲基化模式是长期的、可遗传的特征，能够诱导基因转录发生变化，并且会受到遗传和环境因素的影响。甲基化变化与高血压和动脉粥样硬化有关，这两种疾病都是腹主动脉瘤的危险因素，并且常常与腹主动脉瘤共存。细胞外基质降解和炎症是腹主动脉瘤的两个重要病理特征，在其他疾病中，CpG甲基化的变化也会促进这两个过程。此外，吸烟和衰老的不良影响很大程度上是通过对基因组的表观遗传调控实现的。与腹主动脉瘤相关的每一个因素似乎都与DNA甲基化有关，但尚无直接证据证实这一点。未来确定全基因组甲基化与腹主动脉瘤之间的联系以及差异甲基化区域的研究，可能会揭示有价值的见解。识别出一个共同的表观遗传开关过程，也可能预示着腹主动脉瘤药物治疗策略有光明的未来。目前正在设计针对其他疾病中致病性CpG甲基化变化的表观遗传疗法，这些疗法未来也有可能应用于腹主动脉瘤的治疗。
