Vascular Endothelial Growth Factor Downregulates Apolipoprotein M Expression by Inhibiting Foxa2 in a Nur77-Dependent Manner
Vascular Endothelial Growth Factor Downregulates Apolipoprotein M Expression by Inhibiting Foxa2 in a Nur77-Dependent Manner
复制标题
血管内皮生长因子通过以 Nur77 依赖性方式抑制 Foxa2 下调载脂蛋白 M 表达
DOI：
10.1089/rej.2011.1295
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发表时间：
2012-08-01
影响因子：
2.6
通讯作者：
Bo Si-Tu
中科院分区：
文献类型：
--
作者：
Hu, Yan-Wei;Zheng, Lei;Bo Si-Tu
目的：我们的目的是研究血管内皮生长因子（VEGF）是否影响载脂蛋白M（ApoM）的表达和前β-高密度脂蛋白（HDL）的形成，以及叉头框A2（Foxa 2）和Nur 77是否参与了这一过程。我们分析了264名接受医学检查的成年人的血清VEGF浓度，发现VEGF浓度与血清VEGF浓度呈正相关。甘油三酯、总胆固醇、低密度脂蛋白胆固醇（LDL-C）、极低密度脂蛋白胆固醇（VLDL-C）和ApoB浓度，但与血清高密度脂蛋白胆固醇（HDL-C）和ApoM浓度呈负相关。我们进一步研究了VEGF对HepG 2细胞和小鼠原代肝细胞中ApoM表达和前β-HDL形成的影响及其机制。VEGF显著下调ApoM表达和前β-HDL形成。同时，VEGF还抑制了Foxa 2的表达，而增加了Nur 77的表达。此外，Foxa 2的小干扰（si）RNA敲低使得VEGF对ApoM表达和前β-HDL形成的下调更加明显。此外，Nur 77的siRNA敲低显著补偿了VEGF对Foxa 2表达的抑制作用，而Nur 77激动剂胞孢素B导致Foxa 2表达的下调比VEGF更显著。此外，过度表达的Nur 77转基因在C57 BL/6小鼠导致血清ApoM和前β-HDL水平下降，而si-Nur 77治疗的小鼠显示上调血清ApoM和前β-HDLlevel.Conclusion：这些结果提供了证据，VEGF可能首先通过增强Nur 77活性下调Foxa 2的表达，然后减少ApoM的表达和前β-HDL的形成。因此，我们的研究可能有助于了解VEGF在动脉粥样硬化发病机制中的关键作用。
Objective: We aimed to investigate whether vascular endothelial growth factor (VEGF) influences apolipoprotein M (ApoM) expression and pre-beta-high-density lipoprotin (HDL) formation, and whether forkhead box A2 (Foxa2) and Nur77 are involved in this process.Methods and Results: We analyzed the serum VEGF concentrations of 264 adults who underwent a medical checkup and found that VEGF concentration was positively correlated with serum triglyceride, total cholesterol, LDL cholesterol (LDL-C), very-low-density lipoprotein cholesterol (VLDL-C), and ApoB concentrations, but was negatively correlated with serum high-density lipoprotein cholesterol (HDL-C) and ApoM concentrations. We further investigated the effects of VEGF on ApoM expression and pre-beta-HDL formation, and the mechanisms responsible, in HepG2 cells and mouse primary hepatocytes. VEGF markedly downregulated ApoM expression and pre-beta-HDL formation. At the same time, expression of Foxa2 was also inhibited, whereas expression of Nur77 was increased by treatment with VEGF. Furthermore, small interfering (si) RNA knockdown of Foxa2 made the downregulation of VEGF on ApoM expression and pre-beta-HDL formation even more obvious. In addition, siRNA knockdown of Nur77 significantly compensated for the inhibitory effect of VEGF on Foxa2 expression, whereas the Nur77 agonist cytosporone B led to the downregulation of Foxa2 expression more significantly than VEGF. Moreover, overexpression of a Nur77 transgene in C57BL/6 mice resulted in decreased serum ApoM and pre-beta-HDL levels, whereas si-Nur77-treated mice displayed upregulated serum ApoM and pre-beta-HDL levels.Conclusion: These results provide evidence that VEGF may first downregulate expression of Foxa2 by enhancing Nur77 activity and then decrease expression of ApoM and pre-beta-HDL formation. Therefore, our study may be useful in understanding the critical effect of VEGF in the pathogenesis of atherosclerosis.