代谢调控新因子Irisin延缓血管衰老的作用及机制研究

Vascular aging is one of the important causes of cardio-cerebral vascular diseases. Vascular aging is closely related to activation of Renin-angiotensin (RAS) system. It is well established that exercise delays vascular aging. So, it is very important to explore the functional molecules underlying the beneficial actions of exercise on vascular aging, which may contribute to the prevention and treatment of cardio-cerebral vascular diseases. Irisin is a newly-discovered metabolic active factor that can be induced by exercise. Exercise promotes the release of Irisin from skeletal muscle, which then acts on various metabolic tissues and improves the metabolism. In this preliminary study, we found that Irisin may have a role in delaying vascular aging. To confirm this point, we would test the effects of Irisin on vascualr aging in hypertensive mouse models using Alzet micro-osmotic pump to infuse angiotensin II (in vivo model) and primary cultured vascular endothelial cells/smooth muscle cell model (in vitro model). Moreover, cell senescence staining, gene knockout, treadmill exercise, immunofluorescence, Western blot and other techniques would be used to clarify the underlying molecular mechanisms. Finally, we will try to clarify whether the delay action of exercise on vascular aging are dependent on Irisin. This project may provide experimental evidence for the development of drugs for the treatment of vascular aging, and has important theoretical guidance and potential translational value in therapy of cardio-cerebral vascular diseases.

血管衰老是重大心脑血管疾病的重要诱因，且与肾素-血管紧张素（RAS）系统激活密切相关。运动可延缓血管衰老，但其机制未完全明确。Irisin是一个最新发现的代谢调控因子：在运动时，骨骼肌释放Irisin入血，作用于脂肪、肝脏等，改善糖脂代谢紊乱。本申请人在前期发现，Irisin在血管平滑肌细胞上可显著抑制血管紧张素II（Ang II）导致的血管衰老。基于这一现象，本项目拟在动物、细胞、分子水平，综合运用多种技术手段，包括基因敲除、微渗透泵灌注Ang II诱导血管衰老、β-半乳糖苷酶染色、跑台运动、免疫印迹等，进一步详细阐明Irisin延缓RAS系统激活导致的血管衰老的重要作用，明确运动延缓血管衰老的作用是否依赖于Irisin，并探索Irisin通过调控SIRT6的泛素化发挥抗血管衰老作用的分子机制。这一项目有助于深入理解运动延缓血管衰老的功能分子基础，并有望发现心脑血管重大疾病防治新靶点

背景：.心血管疾病是老年人的头号健康杀手，研究发现，即使在健康的心血管环境中，衰老本身也会逐渐加剧心血管稳态的恶化。血管衰老会造成衰老相关的靶器官损害，直至心血管事件发生和死亡。运动是明确的可以改善血管衰老的措施之一，发现并阐明运动改善血管衰老的新分子机制并针对其进行有效的干预，是重大心脑血管疾病防治中的重要问题。..主要研究内容.在本项目中，我们主要开始以下研究：.(1) 明确新运动因子 Irisin 与运动，年龄之间的相关性；.(2) 使用Irisin的前体FNDC5敲除小鼠，在血管衰老小鼠（in vivo）和细胞模型（in vitro）进行干预，探索Irisin是否能影响血管衰老进程；.(3) 给与运动，或外源性给与Irisin，探索Irisin是否能改善血管衰老。..重要结果.(1) 人体、小鼠验证发现血清Irisin水平与运动呈正相关，与血管衰老程度呈负相关；.(2) 敲除Irisin的前体FNDC5后，Ang-II诱导小鼠动脉衰老加重，血管平滑肌增生减少；.(3) 运动能提高小鼠血清Irisin及主动脉血管组织Irisin前体蛋白FNDC5的表达；.(4) 运动能改善Ang-II诱导的动脉衰老情况及血管平滑肌增殖减少；.(5) 外源性给与Irisin可以拮抗Ang-II 诱导的主动脉衰老。..关键数据及科学意义.我们发现敲除Irisin的前体FNDC5后，Ang-II诱导小鼠动脉衰老加重，且外源性给与Irisin 能够拮抗 Ang-II 诱导的主动脉和血管平滑肌衰老，其延缓血管衰老的机制可能是降低了血管和细胞的炎症和氧化应激水平。我们的结果为探索运动延缓血管衰老中提供有力的证据，具有重要理论意义和潜在的临床应用价值。