动脉粥样硬化治疗新靶点：NAD+-SIRT1信号通路调控巨噬细胞衰老

Atherosclerosis (AS) is the main pathophysiological condition resulting in coronary heart diseases, which remain a heavy health and economic burden globally. Macrophage is the most essential cell type within atherosclerotic lesions. Therefore, it is of importance to find out interventions targeting macrophages for AS treatment. Recent studies revealed the accumulation of senescent cells in atherosclerotic lesions, providing insights into the association between cellular senescence and AS progression. However, the role of senescent macrophages within AS plaques is still unclear. Silent information regulator 1 (SIRT1) is a nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase. Our previous data indicated the anti-senescence effects of NAD+-SIRT1 signaling pathway in macrophages. In the present study, we aimed to demonstrate the potential role of NAD+-SIRT1 signaling pathway against AS via regulating cellular senescence in macrophages, and to clarify the protective effects of NAD+-SIRT1 axis activation. Using the atherosclerotic mice model, the presence and function of cellular senescence in macrophages, and the potential benefits of NAD+-SIRT1 axis activation against AS were examined in vivo. Moreover, the function of cellular senescence in regulating macrophage polarization, inflammatory response, cellular proliferation and apoptosis, as well as the underlying signaling pathway were explored in vitro. Collectively, the present study was designed to reveal the beneficial role of NAD+-SIRT1 signaling pathway against atherogenesis and atherosclerotic progression via regulating cellular senescence in macrophages, which might serve as promising targets for AS treatment. The present study would shed light on novel therapeutic methods for AS.

动脉粥样硬化（atherosclerosis, AS）严重威胁人类健康。巨噬细胞是AS斑块中最重要的细胞类型，因此，针对巨噬细胞的干预手段是AS治疗的关键。最新研究表明，巨噬细胞衰老可能影响其炎症反应及增殖能力，参与斑块进展，值得进一步探究。沉默信息调节因子1（SIRT1）是烟酰胺腺嘌呤二核苷酸（NAD+）依赖的蛋白去乙酰化酶。申请者前期工作提示，NAD+-SIRT1轴是巨噬细胞衰老的关键干预靶点。本研究拟在动物水平，揭示巨噬细胞衰老对AS斑块形成及稳定性的作用，明确是否可以通过外源性激活NAD+-SIRT1轴抑制巨噬细胞衰老，干预斑块进展；在细胞水平，探究细胞衰老对巨噬细胞极化、炎症反应、增殖、凋亡及吞噬功能的影响，并探究NAD+-SIRT1轴的下游分子信号通路。本项目创新性的从巨噬细胞衰老角度探讨NAD+-SIRT1信号通路在AS斑块形成及进展中的作用，为AS治疗提供新思路。

动脉粥样硬化(atherosclerosis，AS)严重威胁人类健康，其临床诊治是医学领域的重大健康问题。沉默信息调节因子1（silent information regulator 1, SIRT1）是烟酰胺腺嘌呤二核苷酸（nicotinamide adenine dinucleotide, NAD+）依赖的蛋白去乙酰化酶，其在AS斑块进展中的作用值得进一步探究。本研究针对SIRT1及Sirtuin家族蛋白在动脉粥样硬化等心血管疾病的病理生理发生、发展过程中的保护作用，在细胞、动物模型和临床样本三个维度上进行了代谢通路分析及分子生物学验证，并且取得了一些较好的研究成果。完成的主要研究工作如下： 1）基于代谢组学方法，对动脉粥样硬化和健康对照组的动物模型及临床样本分析，明确与此相关的代谢通路和关键代谢产物；2）结合代谢组学结果，筛选关键代谢分子花生四烯酸，探究其在动脉粥样硬化动物模型中对SIRT1调控衰老相关分子的作用；3）明确烟酰胺核苷通过外源性激活NAD+-Sirtuin轴，减低细胞氧化应激及炎症反应水平，缓解病理条件下心脏结构重塑和功能障碍，验证NAD+-Sirtuin轴的心血管保护作用。本研究通过临床样本和动物建模，进行了动脉粥样硬化代谢组学分析和分子生物学实验，证实了SIRT1等Sirtuin蛋白在动脉粥样硬化等心血管疾病发展中的作用，为防治动脉粥样硬化提供新的治疗靶标。