Exerkine fibronectin type-III domain-containing protein 5/irisin-enriched extracellular vesicles delay vascular ageing by increasing SIRT6 stability. (5th August 2022)

• Record Type: Journal Article
• Authors: Chi, Chen; Fu, Hui; Li, Yong-Hua; Zhang, Guo-Yan; Zeng, Fei-Yan; Ji, Qing-Xin; Shen, Qi-Rui; Wang, Xu-Jie; Li, Zi-Chen; Zhou, Can-Can; Sun, Di-Yang; Fu, Jiang-Tao; Wu, Wen-Bin; Zhang, Ping-Ping; Zhang, Jia-Bao; Liu, Jian; Shen, Fu-Ming; Li, Dong-Jie; Wang, Pei
• Is Part Of: European heart journal. Volume 43:Number 43(2022)
• Page Start: 4579
• Page End: 4595
• Publication Date: 2022-08-05
• Subjects: Vascular ageing -- Senescence -- Exercise -- Extracellular vesicles -- FNDC5 -- SIRT6; Cardiology -- Periodicals; Heart -- Diseases -- Periodicals; 616.12005
• DOI: 10.1093/eurheartj/ehac431
• Languages: English
• ISSNs: 0195-668X

Abstract

Abstract: 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. Structured Graphical Abstract: Structured Graphical Abstract In response to physical exercise, a metabolically active myokine fibronectin type-III domain-containing 5 (FNDC5)/irisin is stimulated, and packaged into extracellular vesicles (EVs) for secretion into circulation. The FNDC5/irisin-enriched EVs, together with its free form, act on vasculature and delay vascular ageing by increasing SIRT6 stability in a DnaJb3/Hsp40 chaperone-dependent manner. These findings may provide a potential pharmaceutical alternative to address vascular diseases caused by increasingly sedentary lifestyles during the ageing process.