Paradoxic effects of metformin on endothelial cells and angiogenesis.
Paradoxic effects of metformin on endothelial cells and angiogenesis.
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DOI：
10.1093/carcin/bgu001
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发表时间：
2014-05
期刊：
影响因子：
4.7
通讯作者：
Albini A
中科院分区：
文献类型：
--
作者：
Dallaglio K;Bruno A;Cantelmo AR;Esposito AI;Ruggiero L;Orecchioni S;Calleri A;Bertolini F;Pfeffer U;Noonan DM;Albini A
我们研究了二甲双胍对血管生成机制的影响。我们发现，二甲双胍，特别是在肥胖的背景下，在体内抑制血管生成，但对血管生成相关基因和涉及AMPK的蛋白质显示出矛盾的作用。双胍类药物二甲双胍被用于2型糖尿病的治疗，并作为一种潜在的癌症预防药物获得了极大的关注。血管预防代表了化学预防的一种机制，然而关于二甲双胍的抗血管生成作用的矛盾数据已经出现。在这里，我们澄清了二甲双胍对内皮细胞和血管生成的一些相互矛盾的影响，使用体外和体内实验结合转录组学和蛋白质阵列方法。二甲双胍抑制内皮细胞形成毛细血管样网络；这种作用部分依赖于能量传感器腺苷-单磷酸活化蛋白激酶（AMPK），如小干扰RNA敲除所示。人脐静脉内皮细胞的基因表达谱揭示了二甲双胍对几种血管生成相关基因和蛋白的矛盾调节，在信使RNA水平短期诱导血管内皮生长因子（VEGF）、环氧化酶2和CXC趋化因子受体4，并下调ADAMTS1。抗体阵列分析显示，在内皮细胞和乳腺癌细胞中，许多血管生成相关蛋白，包括白细胞介素-8、血管生成素和TIMP-1，以及血管生成素-1、-2、内啡肽等，在本质上是相反的调控。肿瘤细胞上清液以ampk依赖的方式上调内皮细胞细胞色素P450成员CYP1B1的产生，二甲双胍阻断了这一作用。二甲双胍抑制vegf依赖性的细胞外信号调节激酶1/2的激活，而抑制AMPK活性则消除了这一事件。二甲双胍阻碍基质凝胶颗粒体内血管生成，阻止高脂肪饮食肥胖小鼠微血管密度增加，下调白色脂肪组织内皮前体细胞的数量。我们的数据显示，二甲双胍在体外和体内具有抗血管生成活性，这与促血管生成介质的矛盾短期增强以及内皮细胞和乳腺癌细胞的差异调节有关。
We have investigated the effect of metformin on the mechanisms of angiogenesis. We show that metformin, particularly in the context of obesity, inhibits angiogenesis in vivo yet shows a contradictory effect on angiogenesis-related genes and proteins that involve AMPK. The biguanide metformin is used in type 2 diabetes management and has gained significant attention as a potential cancer preventive agent. Angioprevention represents a mechanism of chemoprevention, yet conflicting data concerning the antiangiogenic action of metformin have emerged. Here, we clarify some of the contradictory effects of metformin on endothelial cells and angiogenesis, using in vitro and in vivo assays combined with transcriptomic and protein array approaches. Metformin inhibits formation of capillary-like networks by endothelial cells; this effect is partially dependent on the energy sensor adenosine-monophosphate-activated protein kinase (AMPK) as shown by small interfering RNA knockdown. Gene expression profiling of human umbilical vein endothelial cells revealed a paradoxical modulation of several angiogenesis-associated genes and proteins by metformin, with short-term induction of vascular endothelial growth factor (VEGF), cyclooxygenase 2 and CXC chemokine receptor 4 at the messenger RNA level and downregulation of ADAMTS1. Antibody array analysis shows an essentially opposite regulation of numerous angiogenesis-associated proteins in endothelial and breast cancer cells including interleukin-8, angiogenin and TIMP-1, as well as selective regulation of angiopioetin-1, -2, endoglin and others. Endothelial cell production of the cytochrome P450 member CYP1B1 is upregulated by tumor cell supernatants in an AMPK-dependent manner, metformin blocks this effect. Metformin inhibits VEGF-dependent activation of extracellular signal-regulated kinase 1/2, and the inhibition of AMPK activity abrogates this event. Metformin hinders angiogenesis in matrigel pellets in vivo, prevents the microvessel density increase observed in obese mice on a high-fat diet, downregulating the number of white adipose tissue endothelial precursor cells. Our data show that metformin has an antiangiogenic activity in vitro and in vivo associated with a contradictory short-term enhancement of pro-angiogenic mediators, as well as with a differential regulation in endothelial and breast cancer cells.
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影响因子：
4.5
作者：
Balwierz A;Polus A;Razny U;Wator L;Dyduch G;Tomaszewska R;Scherneck S;Joost H;Dembinska-Kiec A
通讯作者：
Dembinska-Kiec A
DOI：
10.1006/bbrc.1999.1635
发表时间：
1999-11-11
影响因子：
3.1
作者：
Dagher, Z;Ruderman, N;Ido, Y
通讯作者：
Ido, Y
影响因子：
4.8
作者：
Eid, Assaad A.;Ford, Bridget M.;Abboud, Hanna E.
通讯作者：
Abboud, Hanna E.
影响因子：
8.3
作者：
Hattori, Yoshiyuki;Suzuki, Kunihiro;Kasai, Kikuo
通讯作者：
Kasai, Kikuo
影响因子：
9.8
作者：
Abbasi, F;Chu, JW;Reaven, GM
通讯作者：
Reaven, GM