PPAR activators inhibit endothelial cell migration by targeting Akt

详细信息    查看全文

• 作者：Goetze ; Stephan ; Eilers ; Friedrich ; Bungenstock ; Anne ; Kintscher ; Ulrich ; Stawowy ; Philipp ; et. al.
• 关键词：PPARs ; Endothelial cells ; Migration ; ERK MAPK ; Akt
• 刊名：Biochemical and Biophysical Research Communications
• 出版年：2002
• 出版时间：May 24, 2002
• 年：2002
• 卷：293
• 期：5
• 页码：1431-1437
• 全文大小：270 K

文摘

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.