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PPAR activators inhibit endothelial cell migration by targeting Akt

pmid: 12054675
PPAR activators inhibit endothelial cell migration by targeting Akt
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.
- University of California, Los Angeles United States
- University of Chicago United States
Flavonoids, Mitogen-Activated Protein Kinase 1, Lymphokines, Mitogen-Activated Protein Kinase 3, Blotting, Western, Apoptosis, Endothelial Growth Factors, Lipid Metabolism, Fenofibrate, Cell Movement, In Situ Nick-End Labeling, Humans, Hypoglycemic Agents, Peroxisome Proliferators, Endothelium, Vascular, Chromans, Enzyme Inhibitors, Mitogen-Activated Protein Kinases, Cells, Cultured, Hypolipidemic Agents
Flavonoids, Mitogen-Activated Protein Kinase 1, Lymphokines, Mitogen-Activated Protein Kinase 3, Blotting, Western, Apoptosis, Endothelial Growth Factors, Lipid Metabolism, Fenofibrate, Cell Movement, In Situ Nick-End Labeling, Humans, Hypoglycemic Agents, Peroxisome Proliferators, Endothelium, Vascular, Chromans, Enzyme Inhibitors, Mitogen-Activated Protein Kinases, Cells, Cultured, Hypolipidemic Agents
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