PPAR activators inhibit endothelial cell migration by targeting Akt

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Abstract

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 PPARα-activators (fenofibrate, WY14643) and antidiabetic PPARγ-activators (troglitazone, ciglitazone) on this endothelial cell function. Both PPARα- and PPARγ-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 PPARα- and γ-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.

Section snippets

Methods

Materials. Medium 199 Earle and fetal calf serum (FCS) were purchased from Seromed. VEGF, l-glutamine, antibiotics, HEPES, DMSO, insulin, and gelatine were obtained from Sigma. Hybond ECL nitrocellulose membrane, horseradish peroxidase-linked anti-rabbit antibody, as well as ECL Western blotting detection reagents were from Amersham Life Sciences. Wortmannin and WY14643 were from Alexis Biochemicals. Fenofibrate was obtained from Sigma. Ciglitazone was purchased from Biomol. Troglitazone was

PPAR-activators inhibit endothelial cell migration

VEGF-induced migration of HUVEC was potently inhibited by all PPAR-activators tested: the PPARα-activator WY14643 led to a significant inhibition of EC-migration at 20 μmol/L (−67.2±6.5%), while fenofibrate already exerted anti-migratory actions at 10 μmol/L (−54±5.7%) and dramatically inhibited the migration response towards VEGF at 20 μmol/L (−86±4.2%, all p<0.01; Fig. 1). Even more potent effects were observed for the PPARγ-activators troglitazone and ciglitazone that inhibited EC-migration at

Discussion

The present study demonstrates that PPARα- and PPARγ-activators inhibit VEGF-induced endothelial cell migration. We also report that VEGF-induced endothelial cell migration requires activation of the PI3K → Akt and the ERK1/2 MAPK signaling pathway and that PPAR-activators exert their antimigratory effects via inhibition of the protein kinase Akt. Besides their important function in the treatment of metabolic cardiovascular risk factors, an increasing body of evidence points towards a dual

Acknowledgements

The authors would like to thank Mrs. Chantel Spencer-Hänsch for the excellent technical assistance and Mrs. Verena Fromm for her assistance in preparing the manuscript. This study was supported by the Deutsche Forschungsgemeinschaft (DFG GO 800/2-1).

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