Department of Surgery, University of Rochester Medical center, Rochester, NY USA.
Department of Cardiology, Clinical Unit of Internal Medicine, Clinical Hospital Merkur, Zajćeva 19, 10 000 Zagreb, Croatia.
Clin Epigenetics. 2017 Oct 3;9:106. doi: 10.1186/s13148-017-0406-7. eCollection 2017.
Aortic valve stenosis is the most common cardiac valve disease, and with current trends in the population demographics, its prevalence is likely to rise, thus posing a major health and economic burden facing the worldwide societies. Over the past decade, it has become more than clear that our traditional genetic views do not sufficiently explain the well-known link between AS, proatherogenic risk factors, flow-induced mechanical forces, and disease-prone environmental influences. Recent breakthroughs in the field of epigenetics offer us a new perspective on gene regulation, which has broadened our perspective on etiology of aortic stenosis and other aortic valve diseases. Since all known epigenetic marks are potentially reversible this perspective is especially exciting given the potential for development of successful and non-invasive therapeutic intervention and reprogramming of cells at the epigenetic level even in the early stages of disease progression. This review will examine the known relationships between four major epigenetic mechanisms: DNA methylation, posttranslational histone modification, ATP-dependent chromatin remodeling, and non-coding regulatory RNAs, and initiation and progression of AS. Numerous profiling and functional studies indicate that they could contribute to endothelial dysfunctions, disease-prone activation of monocyte-macrophage and circulatory osteoprogenitor cells and activation and osteogenic transdifferentiation of aortic valve interstitial cells, thus leading to valvular inflammation, fibrosis, and calcification, and to pressure overload-induced maladaptive myocardial remodeling and left ventricular hypertrophy. This is especcialy the case for small non-coding microRNAs but was also, although in a smaller scale, convincingly demonstrated for other members of cellular epigenome landscape. Equally important, and clinically most relevant, the reported data indicate that epigenetic marks, particularly certain microRNA signatures, could represent useful non-invasive biomarkers that reflect the disease progression and patients prognosis for recovery after the valve replacement surgery.
主动脉瓣狭窄是最常见的心脏瓣膜病，随着当前人口统计学趋势的发展，其患病率可能会上升，从而给全球社会带来重大的健康和经济负担。在过去的十年中，很明显，我们传统的遗传观点不能充分解释主动脉瓣狭窄与动脉粥样硬化前的危险因素、血流诱导的机械力和易患病的环境影响之间的明显联系。表观遗传学领域的最新突破为我们提供了基因调控的新视角，这拓宽了我们对主动脉瓣狭窄和其他主动脉瓣疾病病因的认识。由于所有已知的表观遗传标记都具有潜在的可逆转性，因此这种观点特别令人兴奋，因为有可能在疾病进展的早期阶段，通过表观遗传水平的成功和非侵入性治疗干预以及细胞的重新编程来开发治疗方法。本文综述了四种主要的表观遗传机制（DNA 甲基化、组蛋白翻译后修饰、ATP 依赖性染色质重塑和非编码调节 RNA）与主动脉瓣狭窄的起始和进展之间的已知关系。大量的分析和功能研究表明，它们可能导致内皮功能障碍、单核细胞-巨噬细胞和循环成骨前体细胞易患病的激活以及主动脉瓣间质细胞的激活和成骨转分化，从而导致瓣膜炎症、纤维化和钙化，以及压力超负荷引起的适应性心肌重构和左心室肥厚。这在小非编码 microRNA 中尤其如此，但对于细胞表观基因组景观的其他成员，也同样如此，尽管规模较小，但也令人信服地证明了这一点。同样重要的是，从临床角度来看，报告的数据表明，表观遗传标记，特别是某些 microRNA 特征，可能代表有用的非侵入性生物标志物，反映疾病进展和患者手术后恢复的预后。
