Oxidized LDL inhibits vascular endothelial growth factor-induced endothelial cell migration by an inhibitory effect on the Akt/endothelial nitric oxide synthase pathway

被引:10
作者
Chavakis, E
Dernbach, E
Hermann, C
Mondorf, UF
Zeiher, AM
Dimmeler, S
机构
[1] Univ Frankfurt, Dept Internal Med 4, Div Mol Cardiol, D-60590 Frankfurt, Germany
[2] Univ Frankfurt, Dept Internal Med 4, Div Nephrol, D-60590 Frankfurt, Germany
关键词
endothelium; lipoproteins; growth substances;
D O I
暂无
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Background-Oxidized LBL (oxLDL) inhibits endothelial cell (EC) migration. Stimulating ECs with vascular endothelial growth factor (VEGF) leads to the activation of Akt/protein kinase B, which in turn activates endothelial nitric oxide synthase (eNOS) by phosphorylation on serine 1177. VEGF-induced cell migration is dependent on the generation of nitric oxide (NO). Therefore, we investigated whether oxLDL affects EC migration by an inhibitory effect on the Akt/eNOS pathway. Methods and Results-During an in vitro "scratched wound assay," oxLDL, dose-dependently inhibited the VEGF-induced migration of human umbilical vein endothelial cells, Western blot analysis revealed that oxLDL dose- and time-dependently led to dephosphorylation and thus deactivation of Akt. Moreover, oxLDL inhibited the VEGF-induced generation of NO, as detected and quantified using a fluorescent NO indicator, 4,5-diaminofluorescein diacetate. Overexpression of a constitutively active Akt construct (Akt T308D/S473D) or a phosphomimetic eNOS construct (eNOS S1177D) almost completely reversed the inhibitory effect of oxLDL on VEGF-induced EC migration and NO generation. Conclusions-Our data indicate that oxLDL-induced dephosphorylation of Akt, followed by impaired eNOS activation: reduces the intracellular level of NO and thereby inhibits VEGF-induced EC migration.
引用
收藏
页码:2102 / 2107
页数:6
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