PPAR activators inhibit endothelial cell migration by targeting Akt
PPAR activators inhibit endothelial cell migration by targeting Akt
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DOI：
10.1016/s0006-291x(02)00385-6
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发表时间：
2002-05-24
影响因子：
3.1
通讯作者：
Gräfe, M
中科院分区：
文献类型：
--
作者：
Goetze, S;Eilers, F;Gräfe, M
过氧化物酶体增殖物激活受体（PPARs）调节脂质和葡萄糖代谢，并发挥多种血管效应，这些效应可能提供这些受体对代谢紊乱和动脉粥样硬化血管疾病的双重益处。内皮细胞迁移是动脉粥样硬化发病机制中的关键事件。因此，我们研究了降脂PPARalpha激活剂（非诺贝特，WY 14643）和抗糖尿病PPARgamma激活剂（曲格列酮，环格列酮）对内皮细胞功能的影响。PPARalpha和PPARgamma激活剂均以浓度依赖性方式显著抑制VEGF诱导的人脐静脉内皮细胞（EC）迁移。已知EC中的趋化性信号传导需要激活两种信号传导途径：磷脂酰肌醇-3-激酶（PI 3 K）-Akt-和ERK 1/2促分裂原活化蛋白激酶（ERK MAPK）途径。使用药理学PI 3 K抑制剂渥曼青霉素和ERK MAPK通路抑制剂PD 98059，我们观察到VEGF诱导的EC迁移的完全抑制。VEGF诱导的Akt磷酸化被PPARalpha和gamma激活剂显著抑制。相反，VEGF刺激的ERK MAPK激活不受任何PPAR激活剂的影响，表明它们抑制ERK MAPK下游或独立于该途径的迁移。这些结果提供了第一个证据的PPAR激活剂在EC中的抗迁移作用。通过抑制EC迁移，PPAR激活剂可以保护血管系统免受与代谢紊乱相关的病理改变。(C)2002 Elsevier Science（美国）。All rights reserved.
Peroxisome proliferator-activated receptors (PPARs) regulate lipid and glucose metabolism and exert several vascular effects that may provide a dual benefit of these receptors on metabolic disorders and atherosclerotic vascular disease. Endothelial cell migration is a key event in the pathogenesis of atherosclerosis. We therefore investigated the effects of lipid-lowering PPARalpha-activators (fenofibrate, WY14643) and antidiabetic PPARgamma-activators (troglitazone, ciglitazone) on this endothelial cell function. Both PPARalpha- and PPARgamma-activators significantly inhibited VEGF-induced migration Of human umbilical vein endothelial cells (EC) in a concentration-dependent manner. Chemotactic signaling in EC is known to require activation of two signaling pathways: the phosphatidylinositol-3-kinase (PI3K) --> Akt- and the ERK1/2 mitogen-activated protein kinase (ERK MAPK) pathway. Using the pharmacological PI3K-inhibitor wortmannin and the ERK MAPK-pathway inhibitor PD98059, we observed a complete inhibition of VEGF-induced EC migration. VEGF-induced Akt phosphorylation was significantly inhibited by both PPARalpha- and gamma-activators. In contrast, VEGF-stimulated ERK MAPK-activation was not affected by any of the PPAR-activators, indicating that they inhibit migration either downstream of ERK MAPK or independent from this pathway. These results provide first evidence for the antimigratory effects of PPAR-activators in EC. By inhibiting EC migration PPAR-activators may protect the vasculature from pathological alterations associated with metabolic disorders. (C) 2002 Elsevier Science (USA). All rights reserved.