Transcriptional Regulation by Angiotensin II in Vascular Smooth Muscle Cells

心血管疾病(心血管疾病)如动脉粥样硬化和高血压是主要的 导致我们社区发病和死亡的原因。此外，这些血管并发症 在糖尿病人群中加速。表观遗传机制已被牵连到 由于环境的影响，包括心血管疾病在内的几种常见的人类疾病 这会影响表观遗传状态。有证据表明，血管紧张素II(Ang II)是一种 由于其血管收缩作用，在高血压和动脉粥样硬化的病理过程中扮演主要角色， 血管等靶细胞的促炎、促氧化和促生长作用 平滑肌细胞(VSMC)。在上一次融资期间，我们报告了第一个 表观遗传的染色质组蛋白修饰和非编码RNA在 调解血管紧张素Ⅱ在血管平滑肌细胞中的一些有害行为。此外，我们的新产品 初步数据表明，Ang II可以调控特定的新的长非编码RNA(LncRNAs)， 和VSMC中调节VSMC相关靶基因表达的增强子 炎症和功能障碍。尽管有这些进展，特定的LncRNA和LncRNA的功能 它们与其他表观遗传因子的微妙相互作用，如调节Ang II诱导的增强子 基因表达仍不完全清楚。此外，促进剂的作用， 血管紧张素Ⅱ介导的VSMC功能障碍及相关心血管疾病中的超增强子和特异性lncRNAs 都是未知的。我们的中心假设是关键的lncRNAs和VSMC的动态控制- 特定的增强子/超增强子，以及这些因素之间的表观遗传串扰， 导致血管紧张素转换酶II诱导的血管平滑肌细胞功能障碍与心血管疾病相关。这将会被测试 通过三个具体目标。在特定的目标1，我们将研究分子机制 我们发现的两个新的血管紧张素Ⅱ诱导的lncRNAs的调节和功能作用 VSMCS。在具体目标2中，我们将定义Ang II调节的增强子和 血管紧张素转换酶II调控基因表达的超增强子参与VSMC功能。在……里面 特异靶向3，两个lncRNAs和候选基因在体内的表达和功能 促进剂/SE将在Ang II诱导的血管功能障碍的小鼠模型中进行检测 动脉硬化。这项研究考察了几个新概念，并使用了创新的平台 通过体内功能模型，获得对VSMC调控网络的新见解。结果是 可能对心血管疾病具有潜在的深远的临床和治疗意义。

Cardiovascular diseases (CVDs) such as atherosclerosis and hypertension are the leading causes of morbidity and mortality in our community. Furthermore these vascular complications are accelerated in the diabetic population. Epigenetic mechanisms have been implicated in several common human diseases, including CVDs, due to the influence of the environment which can affect epigenetic states. Evidence shows that the hormone Angiotensin II (Ang II) is a major player in the pathologies of hypertension and atherosclerosis due to its vasoconstrictive, pro-inflammatory, pro-oxidant, and growth promoting effects in target cells such as vascular smooth muscle cells (VSMC). During the previous funding period, we reported the first functional roles for epigenetic chromatin histone modifications and non-coding RNAs in mediating some of these deleterious actions of Ang II in VSMCs. In addition, our new preliminary data show that Ang II can regulate specific novel long non-coding RNAs (lncRNAs), and enhancers in VSMCs that modulate the expression of target genes associated with VSMC inflammation and dysfunction. Despite these advances, the functions of specific lncRNAs and their subtle interactions with other epigenetic factors like enhancers to modulate Ang II-induced gene expression are still not fully understood. Furthermore, the roles of enhancers, superenhancers and specific lncRNAs in Ang II-mediated VSMC dysfunction and related CVDs are not known. Our central hypothesis is that dynamic control of key lncRNAs and VSMC- specific enhancers/superenhancers, as well as epigenetic cross-talk among these factors, contribute to Ang II-induced VSMC dysfunction associated with CVDs. This will be tested through 3 Specific Aims. In Specific Aim 1, we will examine the molecular mechanisms of regulation and functional roles of two novel lncRNAs that we found to be induced by Ang II in VSMCs. In Specific Aim 2, we will define the roles of Ang II-regulated enhancers and superenhancers in the expression of Ang II-regulated genes involved in VSMC functions. In Specific Aim 3, the in vivo expression and functional roles of the two lncRNAs and candidate enhancers/SEs will be examined in mouse models of Ang II induced vascular dysfunction and atherosclerosis. This study examines several new concepts and uses innovative platforms along with functional in vivo models to gain novel insights into VSMC regulatory networks. The results and can have potentially far reaching clinical and therapeutic implications for CVDs.