Exercise improves angiogenic function of circulating exosomes in type 2 diabetes: Role of exosomal SOD3.
Exercise improves angiogenic function of circulating exosomes in type 2 diabetes: Role of exosomal SOD3.
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DOI：
10.1096/fj.202101323r
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发表时间：
2022-03
期刊：
影响因子：
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通讯作者：
Ushio-Fukai M
中科院分区：
文献类型：
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作者：
Abdelsaid K;Sudhahar V;Harris RA;Das A;Youn SW;Liu Y;McMenamin M;Hou Y;Fulton D;Hamrick MW;Tang Y;Fukai T;Ushio-Fukai M
来源于2型糖尿病（T2 DM）的细胞-细胞通讯的关键介质外泌体表现出有害作用。运动通过分泌外泌体进入循环部分地改善内皮功能。细胞外超氧化物歧化酶（SOD 3）是一种分泌型铜（Cu）抗氧化酶，催化O2·-歧化为H2 O2，其活性依赖于铜转运蛋白ATP 7A。然而，SOD 3在T2 DM中循环血浆外泌体对内皮细胞（EC）的运动诱导的血管生成作用中的作用仍然未知。在这里，我们发现SOD 3和ATP 7A蛋白都存在于小鼠的血浆外泌体中，在两周志愿者车轮运动后显著增加。人类的单次运动也显示出血浆外泌体中SOD 3和ATP 7A蛋白表达的显著增加。来自T2 DM小鼠的血浆外泌体显着降低了人EC或小鼠皮肤伤口愈合模型中的血管生成反应，这与外泌体中ATP 7A表达的降低有关，但与SOD 3表达的降低无关。T2 DM小鼠的运动训练通过增加外泌体中的ATP 7A来恢复EC中T2 DM外泌体的血管生成作用，这在运动的T2 DM/SOD 3 −/−小鼠中没有观察到。此外，过表达SOD 3的外泌体通过以肝素结合结构域依赖性方式增加局部H2 O2水平，显著增强了EC中的血管生成，并恢复了T2 DM或SOD 3 −/−小鼠中有缺陷的伤口愈合和血管生成。总之，运动以SOD 3依赖性方式改善了T2 DM患者循环外泌体的血管生成潜力。外泌体SOD 3可以提供运动模拟疗法，支持心脏代谢疾病中的新血管形成和伤口修复。
Exosomes, key mediators of cell-cell communication, derived from Type 2 diabetes mellitus (T2DM) exhibit detrimental effects. Exercise improves endothelial function in part via secretion of exosomes into circulation. Extracellular superoxide dismutase (SOD3) is a major secretory copper (Cu) antioxidant enzyme that catalyzes the dismutation of O2•- to H2O2 whose activity requires the Cu transporter ATP7A. However, role of SOD3 in exercise-induced angiogenic effects of circulating plasma exosomes on endothelial cells (ECs) in T2DM remains unknown. Here we show that both SOD3 and ATP7A proteins were present in plasma exosomes in mice, which was significantly increased after two weeks volunteer wheel exercise. A single bout of exercise in human also showed a significant increase in SOD3 and ATP7A protein expression in plasma exosomes. Plasma exosomes from T2DM mice significantly reduced angiogenic responses in human ECs or mouse skin wound healing model, which was associated with decrease in ATP7A, but not SOD3 expression in exosomes. Exercise training in T2DM mice restored the angiogenic effects of T2DM exosomes in ECs by increasing ATP7A in exosomes, which was not observed in exercised T2DM/SOD3−/− mice. Furthermore, exosomes overexpressing SOD3 significantly enhanced angiogenesis in ECs by increasing local H2O2 levels in a heparin binding domain-dependent manner as well as restored defective wound healing and angiogenesis in T2DM or SOD3−/− mice. In conclusion, exercise improves the angiogenic potential of circulating exosomes in T2DM in a SOD3-dependent manner. Exosomal SOD3 may provide an exercise mimetic therapy that supports neovascularization and wound repair in cardiometabolic disease.