Vascular endothelial growth factor activates nuclear factor-κB and induces monocyte chemoattractant protein-1 in bovine retinal endothelial cells
Vascular endothelial growth factor activates nuclear factor-κB and induces monocyte chemoattractant protein-1 in bovine retinal endothelial cells
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DOI：
10.2337/diabetes.48.5.1131
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发表时间：
1999-05-01
期刊：
影响因子：
7.7
通讯作者：
Busse, R
中科院分区：
文献类型：
--
作者：
Marumo, T;Schini-Kerth, VB;Busse, R
血管内皮生长因子(VEGF)在糖尿病血管并发症的发病机制中起重要作用。在本研究中，我们研究了牛视网膜微血管内皮细胞(BRECs)中单核细胞趋化蛋白-1(MCP-1)的表达，这种趋化因子被认为是一种将白细胞聚集到炎症、新生血管和血管损伤部位的趋化因子。血管内皮生长因子以浓度和时间依赖的方式诱导BREC MCP-1mRNA的表达。经血管内皮细胞生长因子作用24 h的BRECs分泌MCP-1的量是对照组的2.2倍。转录因子NF-kappaB、N-α-对甲苯磺酰-L赖氨酸氯甲基酮和N-乙酰半胱氨酸的抑制剂以及细胞外信号调节激酶途径的抑制剂PD 98059可减弱血管内皮细胞生长因子诱导的单核细胞趋化蛋白-1mRNA的表达。通过凝胶迁移率改变实验，我们观察到血管内皮生长因子刺激了核因子-kappaB的结合活性，TLCK和Nac抑制了血管内皮生长因子诱导的核因子-kappaB的激活，而PD 98059则不能。转录因子AP-1与核因子-kappaB一起调节MCP-1基因的诱导，其结合活性也被血管内皮生长因子刺激。PD 98059抑制血管内皮细胞生长因子诱导的AP-1活化。这些结果表明，血管内皮细胞生长因子诱导BRECs表达MCP-1很可能是通过激活核因子-kappaB和AP-1，途径不依赖和依赖于ERK。微血管内皮细胞中NF-kappaB的活化和MCP-1的诱导可能参与了糖尿病血管并发症的发生。
Vascular endothelial growth factor (VEGF) has been suggested to play a role in the pathogenesis of diabetic vascular complications. In the present study, we investigated whether expression of monocyte chemoattractant protein-1 (MCP-1), a chemokine that has been proposed to recruit leukocytes to sites of inflammation, neovascularization, and vascular injury, can be modulated by VEGF in bovine retinal microvascular endothelial cells (BRECs). VEGF induced expression of MCP-1 mRNA in BRECs in a concentration- and time-dependent manner. Secretion of MCP-1 into the culture medium of BRECs treated with VEGF for 24 h was increased by 2.2-fold compared with the control. Inhibitors of transcription factor NF-kappa B, N-alpha-tosyl-L-lysine chloromethylketone (TLCK) and N-acetylcysteine (NAC), as well as an inhibitor of the extracellular signal-regulated kinase (ERK) pathway, PD 98059, attenuated VEGF-induced expression of MCP-1 mRNA. Using electrophoretic gel mobility shift assay, we observed that VEGF stimulated binding activity of NF-kappa B. VEGF-induced NF-kappa B activation was inhibited by TLCK and NAC, but not by PD 98059. Binding activity of transcription factor AP-1, which is suggested to regulate induction of the MCP-1 gene together with NF-kappa B, was also stimulated by VEGF. PD 98059 inhibited the VEGF-induced activation of AP-1. These results indicate that VEGF induces MCP-1 expression in BRECs most likely by activating NF-kappa B and AP-1 via ERK-independent and -dependent pathways. Activation of NF-kappa B and induction of MCP-1 by VEGF in microvascular endothelial cells may contribute to the development of diabetic vascular complications.