Modulation of the Cochaperone AHA1 Regulates Heat-Shock Protein 90 and Endothelial NO Synthase Activation by Vascular Endothelial Growth Factor
Modulation of the Cochaperone AHA1 Regulates Heat-Shock Protein 90 and Endothelial NO Synthase Activation by Vascular Endothelial Growth Factor
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DOI：
10.1161/atvbaha.112.256008
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发表时间：
2012-10-01
影响因子：
8.7
通讯作者：
Gratton, Jean-Philippe
中科院分区：
文献类型：
--
作者：
Desjardins, Fanny;Delisle, Chantal;Gratton, Jean-Philippe
血管内皮生长因子（VEGF）信号传导至内皮型一氧化氮合酶（eNOS）在血管生成中起着重要作用。在内皮细胞（EC）中，热休克蛋白90（Hsp 90）也是eNOS活性的调节剂。我们的研究旨在确定Hsp 90 ATP酶1（AHA 1）激活剂的调节是否调节EC中Hsp 90的功能。方法和结果-我们表明，在用针对AHA 1的小干扰RNA转染的EC中，VEGF刺激后Ser-1179上的eNOS磷酸化显着减少。因此，VEGF刺激的NO产生，内皮渗透性，细胞迁移，和EC入侵的基质胶植入物在小鼠中减少小干扰RNA对AHA 1处理的条件。此外，在AHA 1下调的细胞中，VEGF刺激后eNOS与Hsp 90结合的诱导减少。我们还证明，AHA 1调节Hsp 90活性调节酪氨酸-300上的Hsp 90磷酸化。有趣的是，在c-Src介导的Tyr-300上的Hsp 90磷酸化后，AHA 1与Hsp 90的缔合增加。最后，我们表明，AHA 1在内皮细胞的过度表达促进协会的eNOS和热休克蛋白90，磷酸化的Ser-1179 eNOS，增加NO的生产，和细胞migration. Conclusion这些结果表明，AHA 1调节血管内皮生长因子的eNOS和血管生成的热休克蛋白90活性的调制。（Arterioscler Thromb Vasc Biol.2012; 32：2484-2492.）
Objective-Vascular endothelial growth factor (VEGF) signaling to endothelial NO synthase (eNOS) plays a central role in angiogenesis. In endothelial cells (ECs), heat-shock protein 90 (Hsp90) is also a regulator of eNOS activity. Our study is designed to determine whether modulation of the activator of Hsp90 ATPase 1 (AHA1) regulates the function of Hsp90 in ECs.Methods and Results-We show that eNOS phosphorylation on Ser-1179 after VEGF stimulation is significantly reduced in ECs transfected with a small interfering RNA against AHA1. Accordingly, VEGF-stimulated NO production, endothelial permeability, cell migration, and EC invasion in Matrigel implants in mice are reduced in small interfering RNA against AHA1-treated conditions. Furthermore, the induction of eNOS association with Hsp90 after VEGF stimulation is decreased in AHA1-downregulated cells. We also demonstrate that modulation of Hsp90 activity by AHA1 regulates phosphorylation of Hsp90 on Tyr-300. Interestingly, the association of AHA1 with Hsp90 is increased after c-Src-mediated phosphorylation of Hsp90 on Tyr-300. Finally, we show that overexpression of AHA1 in ECs promotes association of eNOS and Hsp90, phosphorylation of Ser-1179 of eNOS, increases NO production, and cell migration.Conclusion-These results reveal that modulation of Hsp90 activity by AHA1 regulates VEGF signaling to eNOS and angiogenesis. (Arterioscler Thromb Vasc Biol. 2012; 32: 2484-2492.)