Age-dependent impairment of endothelial progenitor cells is corrected by growth hormone mediated increase of insulin-like growth factor-1
Age-dependent impairment of endothelial progenitor cells is corrected by growth hormone mediated increase of insulin-like growth factor-1
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DOI：
10.1161/01.res.0000257912.78915.af
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发表时间：
2007-02-16
影响因子：
20.1
通讯作者：
Bauersachs, Johann
中科院分区：
文献类型：
--
作者：
Thum, Thomas;Hoeber, Sarah;Bauersachs, Johann
衰老与动脉粥样硬化风险增加有关。一个可能的原因是内皮祖细胞（EPC）数量少且功能障碍，无法充分修复受损的血管壁。我们假设，随着年龄的增长，胰岛素样生长因子-1 (IGF-1) 水平下降会导致 EPC 功能失调。我们测量了生长激素 (GH) 对小鼠和人类受试者 EPC 的影响，GH 会增加内源性 IGF-1 水平。我们将重组 GH（0.4 mg/d）治疗 10 天前后健康中年男性志愿者（57.4 +/- 1.4 岁）的 EPC 数量和功能与年轻和老年男性受试者（27.5 +/- 0.9 和 74.1 +/- 0.9 岁）的 EPC 数量和功能进行了比较。中老年受试者循环CD133（+）/VEGFR-2（+）EPC较低，功能受损，衰老加剧。中年受试者的 GH 治疗提高了 IGF-1 水平（126.0 +/- 7.2 ng/mL 对比 241.1 +/- 13.8 ng/mL；P < 0.0001），增加了循环 EPC，改善了集落形成和迁移能力，增强了管状结构的掺入，并增强了 EPC 中内皮一氧化氮合酶的表达，与年轻组相当。 GH 处理后 EPC 衰老减弱，而端粒酶活性增加。用 GH（7 天）或 IGF-1 治疗老年小鼠可增加 IGF-1 和 EPC 水平并改善 EPC 功能，而两天 GH 治疗不会改变 IGF-1 或 EPC 水平。使用 IGF-1 对老年个体的 EPC 进行离体治疗可改善功能并减轻细胞衰老。 IGF-1 刺激 EPC 分化、迁移能力以及通过 IGF-1 受体在体外融入形成血管网络的能力。 IGF-1 以磷酸肌醇 3 激酶/Akt 依赖性方式增加 EPC 中的端粒酶活性、内皮一氧化氮合酶表达、磷酸化和活性。小干扰 RNA 介导的 EPC 内皮一氧化氮合酶敲低消除了 IGF-1 的作用。生长激素介导的 IGF-1 增加可逆转与年龄相关的 EPC 功能障碍，并且可能是针对 EPC 损伤的血管疾病的一种新治疗策略。
Aging is associated with an increased risk for atherosclerosis. A possible cause is low numbers and dysfunction of endothelial progenitor cells (EPC) which insufficiently repair damaged vascular walls. We hypothesized that decreased levels of insulin-like growth factor-1 (IGF-1) during age contribute to dysfunctional EPC. We measured the effect of growth hormone (GH), which increases endogenous IGF-1 levels, on EPC in mice and human subjects. We compared EPC number and function in healthy middle-aged male volunteers (57.4 +/- 1.4 years) before and after a 10 day treatment with recombinant GH (0.4 mg/d) with that of younger and elderly male subjects (27.5 +/- 0.9 and 74.1 +/- 0.9 years). Middle-aged and elderly subjects had lower circulating CD133 (+)/VEGFR-2(+) EPC with impaired function and increased senescence. GH treatment in middle-aged subjects elevated IGF-1 levels (126.0 +/- 7.2 ng/mL versus 241.1 +/- 13.8 ng/mL; P < 0.0001), increased circulating EPC with improved colony forming and migratory capacity, enhanced incorporation into tube-like structures, and augmented endothelial nitric oxide synthase expression in EPC comparable to that of the younger group. EPC senescence was attenuated, whereas telomerase activity was increased after GH treatment. Treatment of aged mice with GH ( 7 days) or IGF-1 increased IGF-1 and EPC levels and improved EPC function, whereas a two day GH treatment did not alter IGF-1 or EPC levels. Ex vivo treatment of EPC from elderly individuals with IGF-1 improved function and attenuated cellular senescence. IGF-1 stimulated EPC differentiation, migratory capacity and the ability to incorporate into forming vascular networks in vitro via the IGF-1 receptor. IGF-1 increased telomerase activity, endothelial nitric oxide synthase expression, phosphorylation and activity in EPC in a phosphoinositide-3-kinase/Akt dependent manner. Small interference RNA-mediated knockdown of endothelial nitric oxide synthase in EPC abolished the IGF-1 effects. Growth hormone-mediated increase in IGF-1 reverses age-related EPC dysfunction and may be a novel therapeutic strategy against vascular disorders with impairment of EPC.