Leptin induces endothelial cell migration through Akt, which is inhibited by PPARγ-ligands
Leptin induces endothelial cell migration through Akt, which is inhibited by PPARγ-ligands
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DOI：
10.1161/01.hyp.0000035522.63647.d3
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发表时间：
2002-11-01
期刊：
影响因子：
8.3
通讯作者：
Gräfe, M
中科院分区：
文献类型：
--
作者：
Goetze, S;Bungenstock, A;Gräfe, M
内皮细胞迁移是糖尿病血管病变血管新生的关键环节。瘦素诱导血管生成，并在肥胖和高胰岛素血症中升高。抗糖尿病药物噻唑烷二酮类（TZD）通过激活过氧化物酶体增殖物激活受体-γ（PPARgamma）抑制瘦素基因表达和血管平滑肌细胞迁移。本研究探讨了瘦素在EC迁移中的作用，涉及的趋化信号通路，以及TZD-PPARgamma配体曲格列酮（TRO）和环格列酮（CIG）对EC迁移的影响。我们证明，瘦素诱导EC迁移。由于已知两种信号通路，即磷脂酰肌醇-3激酶（PI 3 K）-Akt-eNOS和ERK 1/2 MAPK通路的激活参与细胞迁移，我们使用药理学抑制剂渥曼青霉素和PD 98059来确定瘦素的趋化信号是否分别涉及Akt或ERK 1/2。渥曼青霉素和PD 98059均显著抑制瘦素诱导的迁移。用TZD-PPAR-γ配体TRO和CIG处理显著抑制了对瘦素的趋化反应。两种PPAR-gamma-配体均抑制瘦素刺激的Akt和eNOS磷酸化，但均不减弱响应瘦素的ERK 1/2活化。Akt磷酸化的抑制伴随着PPAR-γ-配体介导的PTEN上调，PTEN是一种磷酸酶，其作为PI 3 K->Akt信号传导的负调节剂发挥作用。这些实验提供了第一个证据，Akt和ERK 1/2的激活是瘦素介导的信号转导导致EC迁移的关键事件。此外，PPAR-gamma-配体TRO和CIG通过抑制Akt来抑制瘦素定向的迁移强调了它们在预防糖尿病相关并发症中的潜力。
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-gamma (PPARgamma). This study investigates the role of leptin in EC migration, the chemotactic signaling pathways involved, and the effects of the TZD-PPARgamma 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)-->Akt-->eNOS 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-gamma-ligands TRO and CIG significantly inhibited the chemotactic response toward leptin. Both PPAR-gamma-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-gamma-ligand-mediated upregulation of PTEN, a phosphatase that functions as a negative regulator of PI3K-->Akt 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-gamma-ligands TRO and CIG through inhibition of Akt underscores their potential in the prevention of diabetes-associated complications.