Metformin inhibits ALK1-mediated angiogenesis via activation of AMPK.
Metformin inhibits ALK1-mediated angiogenesis via activation of AMPK.
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二甲双胍通过激活 AMPK 抑制 ALK1 介导的血管生成
DOI：
10.18632/oncotarget.15825
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发表时间：
2017-05-16
期刊：
影响因子：
--
通讯作者：
Luo Z
中科院分区：
文献类型：
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作者：
Ying Y;Ueta T;Jiang S;Lin H;Wang Y;Vavvas D;Wen R;Chen YG;Luo Z
抗vegf治疗已被证明是有效的治疗病理性血管生成。然而，治疗抵抗经常发生，导致替代方法的发展。本研究探讨AMPK是否负调控alk1介导的信号事件和相关的血管生成。因此，我们用二甲双胍和其他药理AMPK激活剂处理人脐静脉内皮细胞，发现AMPK的激活可以抑制Smad1/5磷酸化和BMP9诱导的管状形成。AMPKα1活性突变体的表达可以模拟这一事件，而显性的AMPKα1阴性突变体则可以阻止这一事件的发生。二甲双胍对BMP9信号的抑制可能是通过上调Smurf1介导的，从而导致ALK1的降解。此外，二甲双胍抑制bmp9诱导的小鼠基质塞血管生成。采用激光光凝法评价二甲双胍的治疗效果。数据显示，二甲双胍显著降低脉络膜新生血管的水平与ALK1特异性抑制剂LDN212854相当。同时，二甲双胍降低了病变区域内皮中ALK1的表达。总的来说，我们的研究首次证明AMPK抑制ALK1和相关的血管生成/新生血管。这可能为我们在临床上使用的AMPK药理激活剂如二甲双胍联合其他策略来提高治疗效果或抗vegf耐药的情况下治疗相关疾病提供新的途径。
Anti-VEGF therapy has been proven to be effective in the treatment of pathological angiogenesis. However, therapy resistance often occurs, leading to development of alternative approaches. The present study examines if AMPK negatively regulates ALK1-mediated signaling events and associated angiogenesis. Thus, we treated human umbilical vein endothelial cells with metformin as well as other pharmacological AMPK activators and showed that activation of AMPK inhibited Smad1/5 phosphorylation and tube formation induced by BMP9. This event was mimicked by expression of the active mutant of AMPKα1 and prevented by the dominant negative AMPKα1. Metformin inhibition of BMP9 signaling is possibly mediated by upregulation of Smurf1, leading to degradation of ALK1. Furthermore, metformin suppressed BMP9-induced angiogenesis in mouse matrigel plug. In addition, laser photocoagulation was employed to evaluate the effect of metformin. The data revealed that metformin significantly reduced choroidal neovascularization to a level comparable to LDN212854, an ALK1 specific inhibitor. In conjunction, metformin diminished expression of ALK1 in endothelium of the lesion area. Collectively, our study for the first time demonstrates that AMPK inhibits ALK1 and associated angiogenesis/neovascularization. This may offer us a new avenue for the treatment of related diseases using clinically used pharmacological AMPK activators like metformin in combination with other strategies to enhance the treatment efficacy or in the case of anti-VEGF resistance.