Transcriptional Regulation by Angiotensin II in Vascular Smooth Muscle Cells

项目摘要 动脉粥样硬化性和高血压心血管疾病是发病率的主要原因。 和死亡率，以及我们医疗体系的严重压力。多肽激素血管紧张素II (Ang II)由于其收缩血管、促进氧化、促进生长而在这些病理过程中起主要作用。 以及-靶细胞，如血管平滑肌细胞(VSMC)的炎症特性。 一些研究已经证明了Ang II作用的生化和信号机制 通过VSMC的1型受体(AT1R)。然而，精确的核表观遗传机制 参与血管紧张素Ⅱ诱导转录调控的病理基因尚不清楚。它是 越来越多地认识到染色质结构的深刻变化，包括 组蛋白H3-赖氨酸等组蛋白的表观遗传翻译后修饰(PTM) 甲基化(H3Kme)可以调节基因的“活跃”或“不活跃”状态。最近的证据表明 还证明了microRNAs(MiRs)在转录后基因调控中的关键作用 机械装置。我们的目标是评估这种表观遗传和miR机制在血管紧张素转换酶II的作用 以揭开新的治疗靶点。我们假设组蛋白的失调 H3Kme和Key miRs的异常表达参与Ang II诱导的VSMC功能障碍 与各种心血管疾病相关。这将通过三个具体的目标进行测试，使用最先进的 细胞培养中的全基因组图谱和生物信息学方法以及相关小鼠 模特们。具体目的1是对关键染色质组蛋白H3Kme进行表观基因组图谱分析 血管紧张素转换酶II与非血管紧张素转换酶对VSMC的影响 这些标志，然后是它们在VSMC中的功能作用。具体目标2是分析miR 在VSMC中响应Ang II的签名，然后确定密钥的功能相关性 差异表达的miRs。具体目标3是评估特定小鼠模型的增生性 Ang II的作用，以确定表观遗传标记和MIR的体内相关性 在目标1和目标2中发现。完成后，拟议的工作将产生新的新数据 描述血管紧张素转换酶II处理条件下VSMC的表观遗传学和miR谱，以及 将新的下一代基因组测序技术引入血管生物学领域。 这些结果可以增加我们对Ang II行动的理解，并确定可能 可作为高血压和动脉粥样硬化等心血管疾病的临床治疗药物。

Project Summary Atherosclerotic and hypertensive cardiovascular diseases (CVDs) are major causes of morbidity and mortality and a severe strain on our healthcare system. The peptide hormone Angiotensin II (Ang II) plays a major role in these pathologies due to its vasoconstrictive, pro-oxidant, -growth and -inflammatory properties in target cells such as vascular smooth muscle cells (VSMC). Several studies have documented the biochemical and signaling mechanisms of Ang II actions via the type 1 receptor (AT1R) in VSMC. However, the precise nuclear epigenetic mechanisms involved in AngII induced transcriptional regulation of pathological genes are not clear. It is increasingly recognized that profound alterations in chromatin structure, including changes in epigenetic posttranslational modifications (PTMs) of histones, such as Histone H3 -lysine methylation (H3Kme) can regulate the "active" or "inactive" state of genes. Recent evidence has also demonstrated the key roles of microRNAs (miRs) in gene regulation by posttranscriptional mechanisms. Our goal is to evaluate such epigenetic and miR mechanisms in Ang II actions in order to unravel new therapeutic targets. We hypothesize that the dysregulation of histone H3Kme and aberrant expression of key miRs contribute to Ang II induced VSMC dysfunction associated with various CVDs. This will be tested via 3 Specific Aims using state-of-the-art genome-wide profiling and bioinformatics approaches in cell culture along with relevant mouse models. Specific Aim 1 is to perform epigenome profiling of key chromatin histone H3Kme marks in VSMC treated with and without Ang II, evaluate the chromatin enzymes regulating these marks, and then their functional roles in VSMC. Specific Aim 2 is to profile the miR signatures in VSMC in response to Ang II and then determine the functional relevance of key differentially expressed miRs. Specific Aim 3 is to evaluate specific mouse models of increased Ang II action in order to determine the in vivo relevance of the epigenetic marks and miRs uncovered in Aims 1 and 2. When completed, the proposed work will yield novel new data describing the epigenetic and miR profiles of VSMC under Ang II treated conditions, and also bring in new next generation genome sequencing technologies to the field of vascular biology. The results can increase our understanding of Ang II actions, and identify new targets that might be developed as clinical therapies for CVDs such as hypertension and atherosclerosis.