LncRNA SENCR通过抑制VE-Cadherin内吞调控动脉粥样硬化斑块形成的机制研究

SENCR, a human specific cytoplasmic long noncoding RNA (lncRNA), expressed in the vascular endothelial cells and smooth muscle cells. However, its function in endothelial cells remains unclear. In preliminary study, we generated a humanized SENCR transgenic mice (SENCR+/+) and found that SENCR expression level is significantly higher in laminar shear stress (LSS) region compared to disturbed shear stress (DSS) region. Results of Oil-Red O staining also showed that the number of atherosclerosis plaque in the whole aorta isolated from SENCR+/+/ApoE-/- mouse was significantly less than ApoE-/- mouse. In vitro experiments demonstrated that SENCR knock-down in human umbilical vein endothelial cell (HUVEC) induced VE-Cadherin internalization, impaired adherens junction and increased endothelial monolayer permeability. Therefore, we purpose: SENCR regulates vascular endothelial monolayer homeostasis and atherosclerosis through inhibition of VE-Cadherin internalization. In this study, we will use in vitro experiments and animal models to investigate the function and underlying molecular mechanism of SENCR in atherogenesis, providing a new intervention target for atherosclerosis.

SENCR是表达在血管内皮细胞细胞质的人源特异性lncRNA，但其在内皮细胞的功能尚不明确。申请人前期构建人源化SENCR转基因小鼠，发现SENCR表达水平在层流区域显著高于紊流区域且SENCR+/+/ApoE-/-小鼠主动脉斑块与ApoE-/-小鼠相比显著减少。细胞实验发现SENCR敲减导致人脐静脉内皮细胞膜表面的VE-Cadherin内吞增加，细胞黏附连接受损，内皮单细胞层通透性增加。据此提出假设：SENCR通过抑制VE-Cadherin内吞维持内皮层稳态调控动脉粥样硬化斑块形成。本项目拟运用细胞和疾病动物模型，通过组织病理学和分子生物学手段阐明SENCR在动脉粥样硬化斑块形成中的分子机制，为动脉粥样硬化疾病提供新的干预靶点。

动脉粥样硬化相关疾病是导致人口死亡的主要原因之一，尤其是脑卒中、冠心病，显著增加了社会和家庭负担。SENCR是特异性表达在人血管细胞的长链非编码RNA，前期研究揭示SENCR维持血管内皮及平滑肌的功能稳态，申请人通过构建SENCR过表达腺相关病毒，处理Apoe-/-小鼠，提示SENCR具有减轻动脉粥样硬化的作用。在内皮细胞中，SENCR与细胞骨架相关蛋白 4（CKAP4）互作稳定细胞间的黏附连接；而在平滑肌细胞，SENCR结合真核翻译延伸因子1α2（EEF1A2）抑制泛素化激活酶（UBA1）翻译水平，抑制平滑肌细胞的内质网应激。基于脂质纳米颗粒（LNP）递送系统，申请人前期将功能片段SENCR RNA包裹递送（LNP-SENCR），发现LNP-SENCR显著降低了动脉粥样硬化斑块负荷，为治疗动脉粥样硬化提供新的候选药物及方法。此外，还发现了单核细胞亚群上的 ST2L 表达与急性冠状动脉综合征的严重程度和斑块易损性相关；对于居住在社区的中国老年人，每周步行活动与血管靶器官损害呈显著负相关，但与心脏或肾脏靶器官损害无关，增加每日步行时间，但不增加步行频率，与改善血管靶器官损害显著相关。以上论文发表在Archives of Medical Science、Frontiers in Cardiovascular Medicine等杂志上。