LncRNA NBAT1介导的内皮细胞功能的调控在病理剪切力致动脉粥样硬化中的作用与机制

NBAT1 is a newly reported long noncoding RNA, which plays important roles in a variety of tumors. However, its role in atherosclerosis (AS) and the underlying mechanism are still unknown. Pathological shear stress is an important factor leading to the endothelial dysfunction and AS development. Our previous study firstly found that endothelial NBAT1 was upregulated by pathological oscillatory shear stress and in turn promoted endothelial dysfunction; NBAT1 induced the expression of DKK1 which was reported as an atheroprone molecule. But the mechanism in NBAT1-induced DKK1 expression and the roles of NBAT1 in the pathological shear stress-induced AS development still need to be further elucidated. Therefore, the present study is designed to verify the role of NBAT1 in the development of AS at disturbed flow areas both in vivo and in vitro using cell culture, animal model and gene interference et.al methods. We will further investigate the mechanism in the regulation of DKK1 expression by NBAT1 in endothelial cells by use of luciferase reporter gene examination, RIP and RNA dot et.al technology. Our data will provide new information on the biological function of NBAT1, and may be of great value in identification of novel pharmacological intervention strategies.

NBAT1是一种新近发现的与肿瘤相关的长链非编码RNA，其在动脉粥样硬化（AS）中的作用与机制尚不清楚。病理剪切力是导致内皮细胞损伤和AS的重要因素，我们前期研究首次证实内皮细胞NBAT1在病理性震荡剪切力干预下表达上调，促进内皮细胞功能异常；进一步发现NBAT1可诱导致AS作用的分子DKK1的表达，但NBAT1对DKK1的调控机制及其在病理剪切力致内皮细胞损伤与 AS中的作用仍需进一步阐明。为此，本课题将利用体外细胞培养、病理剪切力致AS动物模型构建、基因干扰等方法深入探讨NBAT1在病理剪切力致AS中的作用与机制；并通过荧光素酶报告基因检测、RIP及RNA dot等方法进一步阐明NBAT1作为ceRNA调控内皮细胞DKK1表达的机制。该研究将拓展对 NBAT1生物学功能的新认识，为防治AS提供新的研究方向和干预靶点。

NBAT1是一种新近发现的与肿瘤相关的长链非编码RNA，其在动脉粥样硬化中的作用与机制尚未阐明，血管分叉等处的病理剪切力与动脉粥样硬化的发生发展密切相关。本课题组研究发现，给予体外培养的人血管内皮细胞病理剪切力干预，NBAT1表达显著上调，进而促进内皮细胞凋亡，抑制内皮细胞间紧密连接分子表达，促进内皮细胞功能紊乱；发现DKK1分子介导病理剪切力作用下NBAT1对内皮细胞凋亡及紧密连接分子表达的调控，并进一步揭示了NBAT1通过吸附mir-136-5p进而抑制mir-136-5p与DKK1 3’UTR端靶向结合，促进DKK1转录后翻译的分子机制；体内实验通过慢病载体转染及条件性敲除小鼠模型，进一步证实病理剪切力作用区域mir-136-5p/DKK1轴调控血管内皮细胞凋亡与内皮细胞间紧密连接分子的表达，影响动脉粥样硬化斑块的发生与发展。本研究揭示了病理剪切力通过NBAT1/mir-136-5p/DKK1致动脉粥样硬化发生发展的新机制，为心血管相关疾病的防治提供了新的理论依据与潜在的干预靶点。另外，抗DKK1抗体（BHQ880）目前已作为一种新型药物进入Ⅱ期临床试验，本研究为该药研发过程中可能存在的心血管作用提供了参考价值。