on September 23, 2002
Published online before print September 23, 2002, doi: 10.1161/01.HYP.0000035522.63647.D3
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Submitted on May 9, 2002
From the Department of Medicine/Cardiology, German Heart Institute Berlin (S.G., A.B., F.E., P.S., U.K., C.S.-H., K.G., E.F., M.G.); Department of Pharmacology, Free University Berlin (C.C., B.N.); Institut für Physiologische Chemie II, Universität Düsseldorf, Germany (C.C., B.N.); and Division of Endocrinology, Diabetes, and Hypertension, University of California Los Angeles School of Medicine (R.E.L.), Los Angeles, Calif. * To whom correspondence should be addressed. E-mail: goetze{at}dhzb.de.
Abstract—Migration of endothelial cells (EC) is a key event in angiogenesis that contributes to neovascularization in diabetic vasculopathy. Leptin induces angiogenesis and is elevated in obesity and hyperinsulinemia. The antidiabetic thiazolidinediones (TZD) inhibit leptin gene expression and vascular smooth muscle cell migration through activation of the peroxisome proliferator-activated receptor-
Revised on June 10, 2002
Accepted on August 16, 2002
Leptin Induces Endothelial Cell Migration Through Akt, Which Is Inhibited by PPAR
Stephan Goetze*; 
-Ligands
(PPAR). This study investigates the role of leptin in EC migration, the chemotactic signaling pathways involved, and the effects of the TZD-PPAR ligands troglitazone (TRO) and ciglitazone (CIG) on EC migration. We demonstrate that leptin induces EC migration. Because activation of two signaling pathways, the phosphatidylinositol-3 kinase (PI3K)
AkteNOS and the ERK1/2 MAPK pathway, is known to be involved in cell migration, we used the pharmacological inhibitors wortmannin and PD98059 to determine if chemotactic signaling by leptin involves Akt or ERK1/2, respectively. Both wortmannin and PD98059 significantly inhibited leptin-induced migration. Treatment with the TZD-PPAR-ligands TRO and CIG significantly inhibited the chemotactic response toward leptin. Both PPAR-ligands inhibited leptin-stimulated Akt and eNOS phosphorylation, but neither attenuated ERK 1/2 activation in response to leptin. The inhibition of Akt-phosphorylation was accompanied by a PPAR-ligand-mediated upregulation of PTEN, a phosphatase that functions as a negative regulator of PI3KAkt signaling. These experiments provide the first evidence that activation of Akt and ERK 1/2 are crucial events in leptin-mediated signal transduction leading to EC migration. Moreover, inhibition of leptin-directed migration by the PPAR-ligands TRO and CIG through inhibition of Akt underscores their potential in the prevention of diabetes-associated complications.
Key words: signal transduction • endothelium • kinase • diabetes mellitus • vasculature • phosphorylation
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