LINC00084结合SART3上调eNOS表达维持血管稳态

内皮一氧化氮合酶（eNOS）介导的一氧化氮（NO）产生对维持血管稳态起着关键作用。近年来研究发现：长链非编码RNA（lncRNA）参与基因组修饰和转录功能调节，在内皮功能调控中发挥重要作用。通过系统生物学方法，我们发现内皮富集的lncRNA LINC00084在层流剪切应力和辛伐他汀干预的人内皮细胞中表达上调，但在人和ApoE敲除小鼠的动脉粥样硬化斑块中表达则明显下降。进一步的研究发现LINC00084敲除小鼠内皮细胞eNOS表达下降；LINC00084与SART3相互作用，提示LINC00084可能通过与SART3相互作用促进eNOS表达与活性，从而维持血管稳态。本课题拟利用LINC00084基因敲除小鼠、RNA免疫沉淀等技术，深入研究LINC00084在内皮功能和血管稳态调节中的具体作用及调控机制，为确立以LINC00084为靶标干预内皮功能失调、防治心血管疾病提供更充分的科学依据。

The eNOS-derived nitric oxide (NO) production is essential for vascular homeostasis since reduced NO production and the ensuing endothelial dysfunction underlies the pathology of multiple cardiovascular diseases. Emerging studies have implicated the novel role of long non-coding RNAs in regulating endothelial functions; however, it remains elusive whether there are lncRNAs that can regulate eNOS expression and activity as well as NO production. By completing a next generation RNA-sequencing assay, we found reduced expression of LINC00084 in both mouse and human atherosclerotic plaques. However, LINC00084 expression was up-regulated by atheroprotective laminar flow and simvastatin treatment, implicating the importance of LINC00084 in vascular homeostasis. Our preliminary data have shown that LINC00084 interacts with nuclear RNA-binding protein SART3. We also observed eNOS expression was reduced in the endothelial cells of LINC00084 deficient mice, which further suggests that LINC00084 should be a novel regulator of vascular homeostasis. Therefore, we hypothesize that LINC00084 regulates vascular homeostasis by regulating eNOS expression/function. In this proposal, we will utilize next-generation RNA-sequencing, RNA-protein interaction and knockout mice to study the impact of LINC00084 on endothelial functions and vascular homeostasis. Our study will establish LINC00084 as a new therapeutic target for endothelial dysfunction and associated cardiovascular diseases.