Leonurine Improves Age-Dependent Impaired Angiogenesis: Possible Involvement of Mitochondrial Function and HIF-1α Dependent VEGF Activation.
Leonurine Improves Age-Dependent Impaired Angiogenesis: Possible Involvement of Mitochondrial Function and HIF-1α Dependent VEGF Activation.
复制标题
益母草碱可改善年龄依赖性血管生成受损：可能涉及线粒体功能和 HIF-1 α 依赖性 VEGF 激活
DOI：
10.3389/fphar.2017.00284
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发表时间：
2017
影响因子：
5.6
通讯作者：
Yuan YG
中科院分区：
文献类型：
--
作者：
Qi J;Wang JJ;Duan JL;Lu ZY;Yuan YG
目的：高龄与血管生成受损有关，部分原因是线粒体功能障碍。我们最近报道了益母草碱通过调节线粒体功能发挥神经元保护作用。本研究的目的是探讨益母草碱是否能够减轻老年大鼠后肢缺血的线粒体功能障碍和促进血管生成。方法和结果：术后第14天，与年轻小鼠相比，老年动物缺血肌肉中缺氧诱导因子（HIF）-1α和血管内皮生长因子（VEGF）的表达降低，并伴有氧化应激增强、线粒体损伤增加、毛细血管密度降低和肢体灌注减少。重要的是，这些作用在老年动物中被益母草碱治疗抑制。在体外，我们发现，人脐静脉内皮细胞（HUVECs）的功能活动（迁移和管形成）显着受损，在衰老相比，年轻。然而，益母草碱拯救了衰老HUVEC的功能活动。从机制上讲，我们发现益母草碱恢复了衰老HUVECs中HIF活性的年龄依赖性降低和随后VEGF表达的降低。此外，线粒体氧化应激显着增加衰老的HUVECs，与减少线粒体功能。而益母草碱能显著降低线粒体氧化应激，恢复线粒体膜电位。结论：我们的研究结果表明，益母草碱可能通过减轻线粒体功能障碍和随后的VEGF上调损伤来保护血管生成免受年龄依赖性损伤。
Objective: Advanced age is associated with impaired angiogenesis in part because of mitochondrial dysfunction. We have recently reported that leonurine exerts protective effects in neuron via regulation of mitochondrial function. The aim of this study was to explore whether leonurine is able to attenuate mitochondrial dysfunction and to enhance angiogenesis in old rats with hindlimb ischemia. Methods and Results: At day 14 after surgery, hypoxia-inducible factor (HIF)-1α and vascular endothelial growth factor (VEGF) expression was decreased in the ischemic muscle of aged animals, which was accompanied by enhanced oxidative stress, increased mitochondrial damage, decreased capillary density, and reduced limb perfusion compared with young mice. Importantly, these effects were inhibited by leonurine treatment in old animals. In vitro, we showed that the functional activities (migration and tube formation) of human umbilical vein endothelial cells (HUVECs) were significantly impaired in senescent compared to young. However, leonurine rescued HUVECs functional activities in senescent HUVECs. Mechanistically, we found that leonurine restored the age-dependent reduction in HIF activity and subsequent reduced VEGF expression in senescent HUVECs. Moreover, the mitochondrial oxidative stress was significantly augmented in senescent HUVECs, in association with reduced mitochondrial function. However, leonurine significantly reduced the mitochondrial oxidative stress and restored the mitochondrial membrane potential. Conclusion: Our results demonstrate that leonurine protects against age-dependent impairment of angiogenesis possibly through attenuation of mitochondrial dysfunction and subsequent VEGF up-regulation impairment.