Senescence dysregulates of inflammation-resolution programs in atherosclerosis

动脉粥样硬化性心血管疾病（CVD）是工业化国家的主要死亡原因。失败 慢性炎症反应的消退是慢性炎症进展的重要驱动力。 动脉粥样硬化解决是由专业的亲解决调解员之间的关键平衡调解 （SPM）如脂氧素和消退素以及促炎因子如白三烯（LT）和白藜芦醇 （PG）。我们实验室和其他人以前的工作表明，SPM在斑块中的合成是有缺陷的， SPMs的恢复阻止了小鼠动脉粥样硬化的进展。我们对以下问题的理解仍然存在差距： a）什么细胞过程扰乱了SPM的合成， SPM在动脉粥样硬化中的保护作用。因此 斑块和B）与 本提案的总体目标是了解 动脉粥样硬化中失调消退的新机制和利用新的SPM信号通路 一种新的治疗策略。细胞衰老是一种不可逆的细胞周期停滞，导致细胞高度衰老。 促炎表型称为衰老相关分泌表型（SASP）。突出 衰老细胞（SC）的特征包括升高的COX 2和PG水平以及增强的糖酵解。SCS 最近作为斑块坏死的驱动因素出现，但机制知之甚少。我们的新工作 表明衰老损害内源性解决方案和关键SPM可以限制SASP。 我们提出了一系列的研究，以确定与衰老和受损的机制， 解决（目的I），髓样衰老细胞和斑块中SPM形成之间的联系（目的II）， 高胆固醇血症如何影响衰老和SPM合成的潜在机制（Aim III）。链路 失调的解决方案和衰老之间的关系是一个全新的和未探索的领域， 研究可能揭示动脉粥样硬化的新治疗策略，这些策略与那些 目前存在。

Atherosclerotic cardiovascular disease (CVD) is the leading cause of death in the industrialized world. Failed resolution of a chronic inflammatory response is an important driving force in the progression of atherosclerosis. Resolution is mediated by the critical balance between specialized pro-resolving mediators (SPMs) such as lipoxins and resolvins and pro-inflammatory factors like leukotrienes (LTs) and prostaglandins (PGs). Previous work from our lab and others suggest that SPMs are defectively synthesized in plaques and that restoration of SPMs prevents atherosclerosis progression in mice. Gaps remain in our understanding as to a) what cellular processes derange the synthesis of SPMs in protective actions of SPMs in atherosclerosis. Therefore, the plaques and b) mechanisms associated with the overall objective of this proposal is to understand new mechanisms of dysregulated resolution in atherosclerosis and to harness new SPM signaling pathways towards a novel treatment strategy. Cellular senescence is an irreversible cell cycle arrest that leads to a highly pro-inflammatory phenotype called the senescence-associated secretory phenotype (SASP). Prominent features of senescent cells (SCs) include elevated levels of COX2 and PGs and heightened glycolysis. SCs recently emerged as a driver of plaque necrosis but mechanisms are poorly understood. Our new work suggests that senescence impairs endogenous resolution programs and that key SPMs can limit the SASP. We proposed a series of studies to identify the mechanisms associated with senescence and impaired resolution (Aim I), the link between myeloid senescent cells and SPM formation in plaques (Aim II) and mechanisms underlying how hypercholesterolemia impacts senescence and SPM synthesis (Aim III). The link between dysregulated resolution programs and senescence is a completely new and unexplored area of research that may reveal new treatment strategies for atherosclerosis that are complementary to those that currently exist.