Epigenetic regulation of smooth muscle cell plasticity.
Epigenetic regulation of smooth muscle cell plasticity.
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DOI：
10.1016/j.bbagrm.2014.06.004
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发表时间：
2015-04
期刊：
影响因子：
--
通讯作者：
Martin KA
中科院分区：
文献类型：
--
作者：
Liu R;Leslie KL;Martin KA
平滑肌细胞（SMC）是血管中的主要细胞类型。它们在体内的主要功能是通过血管壁的收缩和松弛来调节血液流动和压力。与成人体内许多其他成熟细胞类型不同，SMC不终末分化，但保留了显著的可塑性。它们具有独特的能力，可以在分化和静止的“收缩”状态和高度增殖和迁移的“合成”表型之间切换，以响应环境压力。虽然通过鉴定影响SMC表型的生长因子和信号，我们对SMC可塑性的理解取得了重大进展，但这些因子和信号如何调节SMC可塑性仍然未知。到目前为止，已经确定了几个关键的转录因子和调节顺式元件在调节SMC状态中起作用。了解SMC可塑性的分子机制的前沿已经发展到表观遗传学的水平。本文将总结SMC的表观遗传调控，重点介绍组蛋白修饰、DNA甲基化的作用，以及我们最近发现的SMC中DNA去甲基化途径，该途径在SMC表型状态的调控中起关键作用。许多疾病都与平滑肌功能障碍有关，包括动脉粥样硬化（中风和冠心病的主要潜在原因），以及移植血管病变、动脉瘤、哮喘、高血压和癌症。增加对SMC可塑性的主要调节因子的了解将导致新的靶分子的鉴定，进而可能导致治疗这些疾病的新药物的发现。
Smooth muscle cells (SMC) are the major cell type in blood vessels. Their principle function in the body is to regulate blood flow and pressure through vessel wall contraction and relaxation. Unlike many other mature cell types in the adult body, SMC do not terminally differentiate but retain a remarkable plasticity. They have the unique ability to toggle between a differentiated and quiescent “contractile” state and a highly proliferative and migratory “synthetic” phenotype in response to environmental stresses. While there have been major advances in our understanding of SMC plasticity through the identification of growth factors and signals that can influence the SMC phenotype, how these regulate SMC plasticity remains unknown. To date, several key transcription factors and regulatory cis elements have been identified that play a role in modulating SMC state. The frontier in understanding the molecular mechanisms underlying SMC plasticity has now advanced to the level of epigenetics. This review will summarize the epigenetic regulation of SMC, highlighting the role of histone modification, DNA methylation, and our most recent identification of a DNA demethylation pathway in SMC that is pivotal in the regulation of the SMC phenotypic state. Many disorders are associated with smooth muscle dysfunction, including atherosclerosis, the major underlying cause of stroke and coronary heart disease, as well as transplant vasculopathy, aneurysm, asthma, hypertension, and cancer. An increased understanding of the major regulators of SMC plasticity will lead to the identification of novel target molecules that may, in turn, lead to novel drug discoveries for the treatment of these diseases.