Bio-Organic Science Division, Korea Research Institute of Chemical Technology, Yuseong-gu, Daejeon 305-600, Korea.
Mol Cell Biochem. 2011 Dec;358(1-2):375-85. doi: 10.1007/s11010-011-0989-9. Epub 2011 Jul 17.
Peroxisome proliferator-activated receptor γ (PPARγ) activation has anti-angiogenic and apoptotic effects in endothelial cells. Here, we investigated the mechanisms of the anti-angiogenic action of a novel PPARγ ligand, KR-62980. KR-62980 inhibited in vitro basal tube formation and in vivo neovascularization in mice induced by Matrigel containing vascular endothelial growth factor (VEGF(165), 5 ng/ml). VEGF(165)-induced cell proliferation and chemotactic migration in human umbilical vein endothelial cells (HUVECs) were also suppressed by KR-62980, in a mechanism accompanied by apoptotic cell death. KR-62980 downregulated the VEGF(165)-induced VEGFR-2 expression but increased the phosphatase and tensin homolog deleted on chromosome 10 (PTEN) expression in parallel with reduced phosphorylation of extracellular signal-related kinase 1/2 (ERK1/2), PI3K p85α, and p38 MAPK. The knockdown of PTEN expression abolished KR-62980-suppressed cell proliferation and angiogenesis. All of the effects of KR-62980 disappeared with pretreatment of bisphenol A diaglycidyl ether (BADGE), a PPARγ antagonist. In summary, KR-62980 inhibited VEGF(165)-induced angiogenesis in HUVECs by PPARγ-mediated dual mechanisms: VEGFR-2 downregulation and PTEN upregulation.
过氧化物酶体增殖物激活受体 γ (PPARγ) 在血管内皮细胞中具有抗血管生成和促凋亡作用。在这里，我们研究了新型 PPARγ 配体 KR-62980 的抗血管生成作用机制。KR-62980 抑制了 Matrigel 中血管内皮生长因子 (VEGF(165)，5ng/ml) 诱导的体外基础管形成和体内新生血管形成。KR-62980 还抑制了 VEGF(165)诱导的人脐静脉内皮细胞 (HUVEC) 增殖和趋化迁移，其机制伴随着细胞凋亡。KR-62980 下调了 VEGF(165)诱导的 VEGFR-2 表达，但同时增加了磷酸酶和张力蛋白同源物缺失的第 10 号染色体 (PTEN) 的表达，从而降低了细胞外信号相关激酶 1/2 (ERK1/2)、PI3K p85α 和 p38 MAPK 的磷酸化。PTEN 表达的敲低消除了 KR-62980 抑制的细胞增殖和血管生成。用双酚 A 二缩水甘油醚 (BADGE)预处理后，KR-62980 的所有作用均消失，BADGE 是一种 PPARγ 拮抗剂。总之，KR-62980 通过 PPARγ 介导的双重机制抑制了 HUVEC 中 VEGF(165)诱导的血管生成：VEGFR-2 下调和 PTEN 上调。
