Zimman Alejandro, Mouillesseaux Kevin P, Le Thang, Gharavi Nima M, Ryvkin Ann, Graeber Thomas G, Chen Tom T, Watson Andrew D, Berliner Judith A
Departments of Medicine, University of California, Los Angeles, CA, USA.
Arterioscler Thromb Vasc Biol. 2007 Feb;27(2):332-8. doi: 10.1161/01.ATV.0000252842.57585.df. Epub 2006 Nov 16.
Previous studies have shown that oxidized products of PAPC (Ox-PAPC) regulate cell transcription of interleukin-8, LDL receptor, and tissue factor. This upregulation takes place in part through the activation of sterol regulatory element-binding protein (SREBP) and Erk 1/2. The present studies identify vascular endothelial growth factor receptor 2 (VEGFR2) as a major regulator in the activation of SREBP and Erk 1/2 in endothelial cells activated by Ox-PAPC.
Ox-PAPC induced the phosphorylation of VEGFR2 at Tyr1175 in human aortic endothelial cells. Inhibitors and siRNA for VEGFR2 decreased the transcription of interleukin-8, LDL receptor, and tissue factor in response to Ox-PAPC and the activation of SREBP and Erk 1/2, which mediate this transcription. We provide evidence that the activation of VEGFR2 is rapid, sustained, and c-Src-dependent.
These data point to a major role of VEGFR2 in endothelial regulation by oxidized phospholipids which accumulate in atherosclerotic lesions and apoptotic cells.
先前的研究表明，血小板激活因子乙酰水解酶的氧化产物（Ox-PAPC）可调节白细胞介素-8、低密度脂蛋白受体和组织因子的细胞转录。这种上调部分是通过固醇调节元件结合蛋白（SREBP）和细胞外信号调节激酶1/2（Erk 1/2）的激活实现的。本研究确定血管内皮生长因子受体2（VEGFR2）是Ox-PAPC激活内皮细胞中SREBP和Erk 1/2的主要调节因子。
Ox-PAPC可诱导人主动脉内皮细胞中VEGFR2的酪氨酸1175位点磷酸化。VEGFR2的抑制剂和小干扰RNA（siRNA）可降低Ox-PAPC诱导的白细胞介素-8、低密度脂蛋白受体和组织因子的转录以及介导该转录的SREBP和Erk 1/2的激活。我们提供的证据表明，VEGFR2的激活迅速、持续且依赖于c-Src。
这些数据表明VEGFR2在氧化磷脂对内皮细胞的调节中起主要作用，氧化磷脂在动脉粥样硬化病变和凋亡细胞中积累。
