MicroRNA-24 Suppression of N-Deacetylase/N-Sulfotransferase-1 (NDST1) Reduces Endothelial Cell Responsiveness to Vascular Endothelial Growth Factor A (VEGFA)
MicroRNA-24 Suppression of N-Deacetylase/N-Sulfotransferase-1 (NDST1) Reduces Endothelial Cell Responsiveness to Vascular Endothelial Growth Factor A (VEGFA)
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DOI：
10.1074/jbc.m113.484360
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发表时间：
2013-09-06
影响因子：
4.8
通讯作者：
Kreuger, Johan
中科院分区：
文献类型：
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作者：
Kasza, Zsolt;Fuchs, Peder Fredlund;Kreuger, Johan
硫酸乙酰肝素(HS)蛋白多糖存在于血管内皮细胞的质膜上，与血管生成因子VEGFA结合，通过VEGFR2调节其信号转导。VEGFA和蛋白多糖共受体之间的相互作用需要HS链上的硫酸化结构域。到目前为止，还不清楚microRNAs如何调控HS中硫酸盐蛋白结合域的形成。在本研究中，我们证明了microRNA-24(miR-24)靶向NDST1可以降低HS的硫酸盐化，从而降低HS与VEGFA的结合亲和力。MiR-24水平升高还导致VEGFR2水平降低和VEGFA信号减弱。同样，使用siRNA抑制NDST1导致VEGFR2表达减少。因此，不仅VEGFA结合，而且VEGFR2蛋白的表达依赖于NDST1的功能。此外，miR-24的过表达，或siRNA介导的NDST1的减少，降低了内皮细胞对VEGFA的趋化反应。这些发现将NDST1确立为miR-24的靶点，并证明了内皮细胞中NDST1的抑制如何导致对VEGFA的反应性降低。
Heparan sulfate (HS) proteoglycans, present at the plasma membrane of vascular endothelial cells, bind to the angiogenic growth factor VEGFA to modulate its signaling through VEGFR2. The interactions between VEGFA and proteoglycan co-receptors require sulfated domains in the HS chains. To date, it is essentially unknown how the formation of sulfated protein-binding domains in HS can be regulated by microRNAs. In the present study, we show that microRNA-24 (miR-24) targets NDST1 to reduce HS sulfation and thereby the binding affinity of HS for VEGFA. Elevated levels of miR-24 also resulted in reduced levels of VEGFR2 and blunted VEGFA signaling. Similarly, suppression of NDST1 using siRNA led to a reduction in VEGFR2 expression. Consequently, not only VEGFA binding, but also VEGFR2 protein expression is dependent on NDST1 function. Furthermore, overexpression of miR-24, or siRNA-mediated reduction of NDST1, reduced endothelial cell chemotaxis in response to VEGFA. These findings establish NDST1 as a target of miR-24 and demonstrate how such NDST1 suppression in endothelial cells results in reduced responsiveness to VEGFA.