Src Plays an Important Role in AGE-Induced Endothelial Cell Proliferation, Migration, and Tubulogenesis.
Src Plays an Important Role in AGE-Induced Endothelial Cell Proliferation, Migration, and Tubulogenesis.
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Src 在 AGE 诱导的内皮细胞增殖、迁移和肾小管形成中发挥重要作用
DOI：
10.3389/fphys.2018.00765
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发表时间：
2018
影响因子：
4
通讯作者：
Guo X
中科院分区：
文献类型：
--
作者：
Li P;Chen D;Cui Y;Zhang W;Weng J;Yu L;Chen L;Chen Z;Su H;Yu S;Wu J;Huang Q;Guo X
晚期糖基化终末产物（AGEs）是在高血糖或氧化应激条件下蛋白质和脂质的非酶促糖基化产生的，其在糖尿病血管并发症（包括糖尿病视网膜病变）的发展中起关键作用。我们以前证明，Src激酶在AGE诱导的人脐静脉内皮细胞（HUVECs）通透性增高和屏障功能障碍中发挥了致病作用。而血管通透性增加是血管新生的早期事件，Src在AGE诱导血管新生中的作用及其机制尚未完全阐明。在这里，我们研究了Src对AGE诱导的HUVECs增殖、迁移和小管形成的影响。用PP 2或siRNA抑制Src可降低AGE诱导的HUVECs迁移和小管形成。pcDNA 3/flag-SrcK 298 M对Src的失活也抑制了AGE诱导的HUVECs增殖、迁移和管腔形成，而pcDNA 3/flag-SrcY 530 F对Src的激活则单独促进了HUVECs的血管生成，并加剧了AGE诱导的血管生成。AGE促进HUVECs体外血管生成的同时伴有ERK的磷酸化。用ERK抑制剂PD 98059抑制ERK可降低AGE诱导的HUVECs血管生成。此外，Src的抑制和沉默抑制了AGE诱导的ERK激活。沉默AGEs受体（AGEs receptor，ERK）也能抑制AGE诱导的ERK激活和血管生成。本研究结果表明Src通过磷酸化ERK在AGE促进HUVECs血管生成中发挥重要作用，并且很可能通过RAGE-Src-ERK途径。
Advanced glycation end products (AGEs), produced by the non-enzymatic glycation of proteins and lipids under hyperglycemia or oxidative stress conditions, has been implicated to be pivotal in the development of diabetic vascular complications, including diabetic retinopathy. We previously demonstrated that Src kinase played a causative role in AGE-induced hyper-permeability and barrier dysfunction in human umbilical vein endothelial cells (HUVECs). While the increase of vascular permeability is the early event of angiogenesis, the effect of Src in AGE-induced angiogenesis and the mechanism has not been completely revealed. Here, we investigated the impact of Src on AGE-induced HUVECs proliferation, migration, and tubulogenesis. Inhibition of Src with inhibitor PP2 or siRNA decreased AGE-induced migration and tubulogenesis of HUVECs. The inactivation of Src with pcDNA3/flag-SrcK298M also restrained AGE-induced HUVECs proliferation, migration, and tube formation, while the activation of Src with pcDNA3/flag-SrcY530F enhanced HUVECs angiogenesis alone and exacerbated AGE-induced angiogenesis. AGE-enhanced HUVECs angiogenesis in vitro was accompanied with the phosphorylation of ERK in HUVECs. The inhibition of ERK with its inhibitor PD98059 decreased AGE-induced HUVECs angiogenesis. Furthermore, the inhibition and silencing of Src suppressed the AGE-induced ERK activation. And the silencing of AGEs receptor (RAGE) inhibited the AGE-induced ERK activation and angiogenesis as well. In conclusions, this study demonstrated that Src plays a pivotal role in AGE-promoted HUVECs angiogenesis by phosphorylating ERK, and very likely through RAGE-Src-ERK pathway.
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影响因子：
10.9
作者：
Manigrasso, Michaele B.;Juranek, Judyta;Ramasamy, Ravichandran;Schmidt, Ann Marie
通讯作者：
Schmidt, Ann Marie
影响因子：
17.8
作者：
Kandarakis, Stylianos A.;Piperi, Christina;Papavassiliou, Athanasios G.
通讯作者：
Papavassiliou, Athanasios G.
DOI：
10.1038/nrm3176
发表时间：
2011-08-23
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
通讯作者：
--
影响因子：
8
作者：
Gray, MJ;Zhang, J;Gallick, GE
通讯作者：
Gallick, GE
影响因子：
11.2
作者：
Golas, JM;Lucas, J;Boschelli, F
通讯作者：
Boschelli, F