Exerkine fibronectin type-III domain-containing protein 5/irisin-enriched extracellular vesicles delay vascular ageing by increasing SIRT6 stability

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.

目的：运动对心血管衰老具有保护作用，但其机制在很大程度上仍不明确。本研究旨在探讨运动相关激素含Ⅲ型纤连蛋白结构域蛋白5（FNDC5）/鸢尾素在血管衰老中的作用。此外，还探究了循环细胞外囊泡（EVs）中FNDC5/鸢尾素的存在及其生物学功能。 方法与结果：在自然衰老、衰老以及血管紧张素II（Ang II）处理的条件下，FNDC5/鸢尾素减少。FNDC5的缺失缩短了小鼠的寿命。此外，在24月龄自然衰老和Ang II处理的小鼠中，FNDC5缺乏加重了血管僵硬、衰老、氧化应激、炎症和内皮功能障碍。相反，重组鸢尾素治疗缓解了Ang II诱导的小鼠和血管平滑肌细胞的血管僵硬和衰老。运动可触发FNDC5，而FNDC5基因敲除消除了运动对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EVs中检测到了FNDC5，并且运动诱导的富含FNDC5/鸢尾素的EVs在体内和体外均显示出强大的抗僵硬和抗衰老作用。在FNDC5基因敲除小鼠中，腺相关病毒介导的FNDC5在肌肉（而非肝脏）中的特异性恢复，促进了富含FNDC5/鸢尾素的EVs在运动时释放到循环中，从而改善了血管僵硬、衰老和炎症。从机制上讲，鸢尾素以热休克蛋白70（Hsp70）依赖的方式激活DnaJb3/热休克蛋白40（Hsp40）伴侣系统以稳定SIRT6蛋白。最后，在一项概念验证的人体研究中，血浆鸢尾素浓度与运动时间呈正相关，与动脉僵硬呈负相关。 结论：富含FNDC5/鸢尾素的EVs有助于运动诱导的对血管衰老的保护作用。这些发现表明，运动因子FNDC5/鸢尾素可能是与衰老相关的血管合并症的一个潜在靶点。