Visfatin induces human endothelial VEGF and MMP-2/9 production via MAPK and PI3K/Akt signalling pathways: novel insights into visfatin-induced angiogenesis
Visfatin induces human endothelial VEGF and MMP-2/9 production via MAPK and PI3K/Akt signalling pathways: novel insights into visfatin-induced angiogenesis
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DOI：
10.1093/cvr/cvm111
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发表时间：
2008-05-01
影响因子：
10.8
通讯作者：
Randeva, Harpal S.
中科院分区：
文献类型：
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作者：
Adya, Raghu;Tan, Bee K.;Randeva, Harpal S.
内脂素是一种新的脂肪因子，其血浆浓度在肥胖和肥胖相关疾病中发生改变;这些状态与心血管疾病的发病率增加有关。因此，我们研究了内脂素对血管内皮生长因子（VEGF）和基质金属蛋白酶的影响。方法和结果在人脐静脉内皮细胞（HUVEC）中，内脂素可剂量依赖性地上调VEGF和MMPS的基因表达和蛋白生成，下调MMPs组织抑制因子的表达（TIMP-1和TIMP-2）。MMP的明胶分解活性（通过酶谱分析）与mRNA和蛋白质印迹结果相关。有趣的是，内脂素显著上调VEGF受体2的表达。抑制VEGFR 2和VEGF [通过可溶性FMS样酪氨酸激酶-1（sFlt 1）]下调visfatin诱导的MMP诱导。内脂素诱导的增殖和毛细血管样管形成的剂量和时间依赖性。重要的是，内脂素具有抗凋亡作用。在HUVECs中，内脂素剂量依赖性地激活PI 3 K/Akt（磷脂酰肌醇3-激酶/Akt）和ERK 1/2（细胞外信号调节激酶）通路。功能效应和MMP/VEGF诱导显示依赖于MAPK/PI 3 K-Akt/VEGF信号通路。抑制PI 3 K/Akt和ERK 1/2通路可显著降低visfatin诱导的MMP和VEGF的产生和活化，沿着内皮细胞增殖和毛细血管形成的减少。此外，我们首次表明MAPK和PI 3 K/Akt信号通路参与介导这些作用，以及内皮细胞增殖。总的来说，我们的研究结果提供了新的见解visfatin诱导的内皮血管生成。
Aims Visfatin is a novel adipokine whose plasma concentrations are altered in obesity and obesity-related disorders; these states are associated with an increased incidence of cardiovascular disease. We therefore investigated the effect of visfatin on vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMP-2, MMP-9) production and the potential signalling cascades.Methods and results In human umbilical vein endothelial cells (HUVECs), visfatin significantly and dose-dependently up-regulated gene expression and protein production of VEGF and MMPS and down-regulated expression of tissue inhibitors of MMPs (TIMP-1 and TIMP-2). The gelatinolytic activity of MMPs (analysed by zymography) correlated with mRNA and western blot findings. Interestingly, visfatin significantly up-regulated VEGF receptor 2 expression. Inhibition of VEGFR2 and VEGF [by soluble FMS-like tyrosine kinase-1 (sFlt1)] down-regulated visfatin-induced MMP induction. Visfatin induced dose-and time-dependent proliferation and capillary-like tube formation. Importantly, visfatin was noted to have anti-apoptotic effects. In HUVECs, visfatin dose-dependently activated PI3K/Akt (phosphatidylinositol 3-kinase/Akt) and ERK1/2 (extracellular signal-regulated kinase) pathways. The functional effects and MMP/VEGF induction were shown to be dependent on the MAPK/PI3K-Akt/VEGF signalling pathways. Inhibition of PI3K/Akt and ERK1/2 pathways led to significant decrease of visfatin-induced MMP and VEGF production and activation, along with significant reduction in endothelial proliferation and capillary tube formation.Conclusion Our data provide the first evidence of visfatin-induced endothelial VEGF and AAMP production and activity. Further, we show for the first time the involvement of the MAPK and PI3K/Akt signalling pathways in mediating these actions, as welt as endothelial cell proliferation. Collectively, our findings provide novel insights into visfatin-induced endothelial angiogenesis.