UHRF1 epigenetically orchestrates smooth muscle cell plasticity in arterial disease
UHRF1 epigenetically orchestrates smooth muscle cell plasticity in arterial disease
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DOI：
10.1172/jci96121
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发表时间：
2018-06-01
影响因子：
15.9
通讯作者：
Quintavalle, Manuela
中科院分区：
文献类型：
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作者：
Elia, Leonardo;Kunderfranco, Paolo;Quintavalle, Manuela
成体血管平滑肌细胞（VSMC）对细胞外信号（如血管损伤和炎症）的反应是去分化。去分化的VSMC是增殖性的、迁移性的、收缩性较低的，并且可以有助于血管修复以及心血管病理学，例如冠状动脉和动脉瘤中的内膜增生/再狭窄。我们在这里展示了泛蛋白样的PHD和环指结构域1（UHRF 1）作为VSMC可塑性的表观遗传主调节器的作用。UHRF 1的表达与血管病变的发展相关，血管病变与非编码RNA（如microRNA）的调节有关。miR-145-调节VSMC可塑性的关键，在血管疾病中减少-被发现控制Uhrf 1 mRNA的翻译。反过来，UHRF 1触发VSMC增殖，直接抑制细胞周期抑制基因（包括p21和p27）的启动子，并通过DNA和组蛋白的甲基化关键的促分化基因。Uhrf 1 shRNA或Uhrf 1 VSMC特异性缺失的局部血管病毒递送防止小鼠颈动脉内膜增生，并减少小鼠主动脉瘤模型中的血管损伤。我们的研究表明，Uhrf 1在调节VSMC表型，促进增殖和去分化的基本作用。UHRF 1靶向可能在血管病变中具有治疗潜力。
Adult vascular smooth muscle cells (VSMCs) dedifferentiate in response to extracellular cues such as vascular damage and inflammation. Dedifferentiated VSMCs are proliferative, migratory, less contractile, and can contribute to vascular repair as well as to cardiovascular pathologies such as intimal hyperplasia/restenosis in coronary artery and arterial aneurysm. We here demonstrate the role of ubiquitin-like containing PHD and RING finger domains 1 (UHRF1) as an epigenetic master regulator of VSMC plasticity. UHRF1 expression correlated with the development of vascular pathologies associated with modulation of noncoding RNAs, such as microRNAs. miR-145-pivotal in regulating VSMC plasticity, which is reduced in vascular diseases-was found to control Uhrf1 mRNA translation. In turn, UHRF1 triggered VSMC proliferation, directly repressing promoters of cell-cycle inhibitor genes (including p21 and p27) and key prodifferentiation genes via the methylation of DNA and histones. Local vascular viral delivery of Uhrf1 shRNAs or Uhrf1 VSMC-specific deletion prevented intimal hyperplasia in mouse carotid artery and decreased vessel damage in a mouse model of aortic aneurysm. Our study demonstrates the fundamental role of Uhrf1 in regulating VSMC phenotype by promoting proliferation and dedifferentiation. UHRF1 targeting may hold therapeutic potential in vascular pathologies.