Central Laboratory, The First College of Clinical Medical Science, China Three Gorges University & Yichang Central People's Hospital, Yichang, 443003, China; Department of Cardiology, The First College of Clinical Medical Science, China Three Gorges University & Yichang Central People's Hospital, Yichang, 443003, China.
Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, 430060, China.
Atherosclerosis. 2019 Sep;288:76-84. doi: 10.1016/j.atherosclerosis.2019.06.909. Epub 2019 Jun 20.
Neointimal hyperplasia resulting from pathological vascular smooth muscle cells (VSMCs) activation is a common pathophysiological basis for numerous proliferative vascular diseases, such as restenosis. Suv39h1, an important transcription suppressor, may be involved in this process. Herein, we investigated the role of Suv39h1 in pathological intimal hyperplasia and its possible mechanisms in vitro and in vivo.
An adenovirus vector for Suv39h1 overexpression and a lentiviral vector for its downregulation were constructed and used to transfect cultured VSMCs in vitro. The functional changes in VSMCs stimulated by angiotensin II (Ang II) were observed and the possible mechanism was investigated. Additionally, rat carotid arteries with balloon injury were locally transfected with these viral vectors and changes in neointima formation, proliferating cell nuclear antigen (Pcna) expression and collagen deposition were examined.
Upon Ang II stimulation, the expression of Suv39h1 and inhibitor of DNA binding 3 (Id3) was significantly increased. Suv39h1 downregulation inhibited Ang II-stimulated migration and proliferation of VSMCs, antagonized the production of Id3 and promoted p21 and p27Kip1 expression. In contrast, Suv39h1 overexpression had the opposite effects. Suv39h1 regulated the transcription of p21 and p27Kip1 by controlling H3K9me3 in the proximal promoter regions. Consistent with the VSMCs results, Suv39h1 and Id3 expression was significantly increased in blood vessels after balloon injury. Suv39h1 downregulation inhibited intimal hyperplasia, and attenuated Pcna expression and collagen synthesis in the intima, while Suv39h1 overexpression had the opposite effects.
Suv39h1 downregulation effectively inhibited neointimal hyperplasia after vascular injury.
病理性血管平滑肌细胞（VSMCs）激活导致的新生内膜增生是多种增殖性血管疾病（如再狭窄）的常见病理生理基础。Suv39h1 是一种重要的转录抑制因子，可能参与这一过程。本研究旨在探讨 Suv39h1 在病理性内膜增生中的作用及其在体内外的可能机制。
构建 Suv39h1 过表达的腺病毒载体和下调其表达的慢病毒载体，体外转染血管平滑肌细胞，观察血管紧张素 II（Ang II）刺激下 VSMCs 的功能变化，并探讨其可能的机制。此外，采用这些病毒载体局部转染大鼠颈动脉损伤模型，观察新生内膜形成、增殖细胞核抗原（Pcna）表达和胶原沉积的变化。
Ang II 刺激后，Suv39h1 和 DNA 结合抑制因子 3（Id3）的表达明显增加。下调 Suv39h1 抑制 Ang II 刺激的 VSMCs 迁移和增殖，拮抗 Id3 的产生，促进 p21 和 p27Kip1 的表达。相反，过表达 Suv39h1 则有相反的作用。Suv39h1 通过控制近端启动子区域的 H3K9me3 来调节 p21 和 p27Kip1 的转录。与 VSMCs 结果一致，球囊损伤后血管中 Suv39h1 和 Id3 的表达明显增加。下调 Suv39h1 抑制血管损伤后的内膜增生，并减弱内膜中 Pcna 表达和胶原合成，而过表达 Suv39h1 则有相反的作用。
下调 Suv39h1 可有效抑制血管损伤后的新生内膜增生。
