Aims Exercise confers protection against cardiovascular ageing, but the mechanisms remain largely unknown. This study sought to investigate the role of fibronectin type-III domain-containing protein 5 (FNDC5)/irisin, an exercise-associated hormone, in vascular ageing. Moreover, the existence of FNDC5/irisin in circulating extracellular vesicles (EVs) and their biological functions was explored. Methods and results FNDC5/irisin was reduced in natural ageing, senescence, and angiotensin II (Ang II)-treated conditions. The deletion of FNDC5 shortened lifespan in mice. Additionally, FNDC5 deficiency aggravated vascular stiffness, senescence, oxidative stress, inflammation, and endothelial dysfunction in 24-month-old naturally aged and Ang II-treated mice. Conversely, treatment of recombinant irisin alleviated Ang II-induced vascular stiffness and senescence in mice and vascular smooth muscle cells. FNDC5 was triggered by exercise, while FNDC5 knockout abrogated exercise-induced protection against Ang II-induced vascular stiffness and senescence. Intriguingly, FNDC5 was detected in human and mouse blood-derived EVs, and exercise-induced FNDC5/irisin-enriched EVs showed potent anti-stiffness and anti-senescence effects in vivo and in vitro. Adeno-associated virus-mediated rescue of FNDC5 specifically in muscle but not liver in FNDC5 knockout mice, promoted the release of FNDC5/irisin-enriched EVs into circulation in response to exercise, which ameliorated vascular stiffness, senescence, and inflammation. Mechanistically, irisin activated DnaJb3/Hsp40 chaperone system to stabilize SIRT6 protein in an Hsp70-dependent manner. Finally, plasma irisin concentrations were positively associated with exercise time but negatively associated with arterial stiffness in a proof-of-concept human study. Conclusion FNDC5/irisin-enriched EVs contribute to exercise-induced protection against vascular ageing. These findings indicate that the exerkine FNDC5/irisin may be a potential target for ageing-related vascular comorbidities.

中文翻译：

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Exerkine 纤连蛋白 III 型结构域含蛋白 5/富含鸢尾素的细胞外囊泡通过增加 SIRT6 稳定性来延缓血管老化

目的 运动可以防止心血管老化，但其机制在很大程度上仍不为人知。本研究旨在探讨含纤连蛋白 III 型结构域的蛋白 5 (FNDC5)/鸢尾素（一种运动相关激素）在血管老化中的作用。此外，还探讨了循环细胞外囊泡 (EV) 中 FNDC5/鸢尾素的存在及其生物学功能。方法和结果 FNDC5/鸢尾素在自然老化、衰老和血管紧张素 II (Ang II) 处理的条件下减少。FNDC5 的缺失缩短了小鼠的寿命。此外，FNDC5 缺乏会加重 24 个月大的自然衰老和 Ang II 治疗小鼠的血管僵硬、衰老、氧化应激、炎症和内皮功能障碍。反过来，重组鸢尾素的治疗减轻了 Ang II 诱导的小鼠和血管平滑肌细胞的血管僵硬和衰老。FNDC5 由运动触发，而 FNDC5 敲除消除了运动诱导的针对 Ang II 诱导的血管僵硬和衰老的保护作用。有趣的是，在人和小鼠血液来源的 EV 中检测到 FNDC5，并且运动诱导的富含 Irisin 的 EV 在体内和体外显示出有效的抗僵硬和抗衰老作用。腺相关病毒介导的 FNDC5 拯救，特别是在 FNDC5 敲除小鼠的肌肉而非肝脏中，促进富含 FND​​C5/鸢尾素的 EV 释放到循环中以响应运动，从而改善血管僵硬、衰老和炎症。从机械上讲，鸢尾素激活 DnaJb3/Hsp40 伴侣系统，以 Hsp70 依赖性方式稳定 SIRT6 蛋白。最后，在一项概念验证人体研究中，血浆鸢尾素浓度与运动时间呈正相关，但与动脉硬度呈负相关。结论 富含 FND​​C5/鸢尾素的 EV 有助于运动诱导的血管老化保护。这些发现表明，exerkine FNDC5/irisin 可能是与衰老相关的血管合并症的潜在靶标。