miR-181b, endothelial cells, and vascular inflammation

内皮细胞(EC)的激活和功能障碍随着年龄的增长而增加，并与各种慢性血管疾病有关 包括动脉粥样硬化在内的炎症性疾病状态是西方国家发病率和死亡率的主要原因 社会。DNA损伤反应(DDR)诱导的血管衰老促进慢性炎症 在动脉粥样硬化病变中。衰老相关的促炎细胞因子和动脉粥样硬化危险因素 (获得性或遗传性)，如高脂血症激活关键信号通路，增加 黏附分子，几种细胞类型上的趋化因子，包括血管内皮细胞。因此， 抑制血管内皮细胞衰老相关的炎症反应可能提供一种 限制动脉粥样硬化的新治疗方法。 MicroRNAs(MiRNAs)是一种小的、单链的、进化保守的非编码RNA 在转录后水平抑制靶基因的表达，并参与多种 病理生理过程，包括炎症反应的调节。我们的团队提供了首个 提示miR-181b参与抑制内皮细胞炎症。在上一次授权期内，我们 通过对两种内皮细胞静止的调节作用，确定miR-181b为内皮细胞静止的结节调节因子 主要信号转导通路--核因子-κB和AKT/eNOS。因此，内源性miR-181b被发现 作为体内炎症反应的关键决定因素，与人类相关的发现 炎症状态，包括已确诊的冠状动脉疾病。我们现在确定内皮细胞miR-181b是一种 控制血管衰老是全身血管炎症和动脉粥样硬化的关键决定因素 以及DNA损伤反应。此外，我们还证明了腺苷-A3AR信号通路，a 抑制内皮细胞激活的翻译相关靶点，在miR-181b依赖中发挥作用 举止。这些观察结果为中心假设提供了基础，即内皮miR-181b通过 抑制DNA损伤反应，调节衰老相关的血管炎症和 动脉硬化。为了更好地了解miR-181b在调节血管衰老中的确切作用， 炎症和动脉粥样硬化，我们提出了三个目标。在Aim1中，我们将确定miR-的分子基础 181b调节DNA损伤反应和血管衰老对不同刺激的反应。在Aim2， 我们将探讨改变miR-181b表达对衰老相关分泌表型和 年轻和老年小鼠动脉粥样硬化的进展和消退。在Aim3中，我们将确定是否 腺苷在血管内皮细胞的抗衰老作用依赖miR-181b。这一多学科的 在非编码RNA生物学、分子成像、纳米医学、生物信息学和 动脉粥样硬化研究将建立一种前所未有的关于这种miRNA的分子观点，它可以 在调节血管衰老和动脉粥样硬化方面开辟了新的前沿。

Endothelial cell (EC) activation and dysfunction increases with age and is linked to a variety of chronic vascular inflammatory disease states including atherosclerosis—the major cause of morbidity and mortality in Western Societies. Vascular senescence induced by the DNA damage response (DDR) promotes chronic inflammation in atherosclerotic lesions. Senescence-associated proinflammatory cytokines and proatherogenic risk factors (acquired or inherited) such as hyperlipidemia activate key signaling pathways that increase expression of adhesion molecules, chemokines on several cell types, including the vascular endothelium. Therefore, suppressing the senescence-associated inflammatory response in the vascular endothelium may provide a novel therapeutic approach to limit atherosclerosis. MicroRNAs (miRNAs) are small, single-stranded, evolutionary conserved non-coding RNAs that suppress the expression of target genes at the post-transcriptional level and participates in a variety of pathophysiological processes including the regulation of inflammatory responses. Our group provided the initial link implicating miR-181b in suppressing endothelial cell inflammation. During the last grant period, we identified miR-181b as a nodal regulator of endothelial cell quiescence through its regulatory effects on two major signaling pathways – NF-κB and AKT/eNOS. Consequently, endogenous miR-181b was found to function as a key determinant of the inflammatory response in vivo, findings that correlate with human inflammatory states including established coronary artery disease. We now identify endothelial miR-181b as a critical determinant of systemic vascular inflammation and atherosclerosis by controlling vascular senescence and the DNA damage response. Furthermore, we demonstrate that the adenosine-A3AR signaling pathway, a translationally relevant target that suppresses endothelial activation, functions in a miR-181b-dependent manner. These observations provide the foundation for the central hypothesis that endothelial miR-181b, via inhibitory effects on the DNA damage response, regulates senescence-associated vascular inflammation and atherosclerosis. To better understand the precise role of miR-181b in regulating vascular senescence, inflammation, and atherosclerosis, we propose 3 aims. In Aim1, we will determine the molecular basis for miR- 181b to regulate the DNA damage response and vascular senescence in response to diverse stimuli. In Aim2, we will explore the effect of altering miR-181b expression on senescence-associated secretory phenotype and atherosclerotic progression and regression in young and aged mice. In Aim3, we will determine whether the anti-senescent effects of adenosine in the vascular endothelium depend on miR-181b. This multi-disciplinary team in the fields of non-coding RNA biology, molecular imaging, nanomedicine, bioinformatics, and atherosclerosis research will establish an unprecedented molecular view of this miRNA in lesions that can inform a new frontier in the regulation of vascular senescence and atherosclerosis.