Geranylgeranylacetone, Heat Shock Protein 90/AMP-Activated Protein Kinase/Endothelial Nitric Oxide Synthase/Nitric Oxide Pathway, and Endothelial Function in Humans
Geranylgeranylacetone, Heat Shock Protein 90/AMP-Activated Protein Kinase/Endothelial Nitric Oxide Synthase/Nitric Oxide Pathway, and Endothelial Function in Humans
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DOI：
10.1161/atvbaha.111.237263
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发表时间：
2012-01-01
影响因子：
8.7
通讯作者：
Higashi, Yukihito
中科院分区：
文献类型：
--
作者：
Fujimura, Noritaka;Jitsuiki, Daisuke;Higashi, Yukihito
β-香叶基香叶基丙酮（GGA）诱导热休克蛋白90（Hsp 90）的表达，热休克蛋白90是一种用于组装内皮型一氧化氮合酶（eNOS）磷酸化复合物的衔接分子。本研究的目的是确定是否GGA增强热休克蛋白90的表达和增强内皮依赖性血管舒张通过上调eNOS在human.Methods和结果，我们评估了GGA对人脐静脉内皮细胞（HUVECs）和前臂血流（FBF）的影响，乙酰胆碱和硝普钠在40个健康的年轻男子。Western blot检测HUVECs和外周血单个核细胞中Hsp 90、eNOS、AMPK和Akt的表达。GGA增加HUVECs中Hsp 90的表达和eNOS和AMPK的磷酸化，但不增加Akt，并增加外周血单个核细胞中Hsp 90的表达。口服GGA（600 mg）增强FBF对乙酰胆碱的反应。输注NO合酶抑制剂N（G）-单甲基-L-精氨酸，完全消除了GGA诱导的FBF对乙酰胆碱的反应增强。GGA还增强了乙酰胆碱刺激的NO释放在smokers. Conclusion这些研究结果表明，GGA诱导的激活Hsp 90/AMPK显着增加NO介导的血管舒张在健康受试者，以及在吸烟者。GGA的使用可能是改善内皮功能障碍的一种新的治疗方法。（Arterioscler Thromb Vasc Biol.2012;32：153-160.）
Objective-Geranylgeranylacetone (GGA) induces expression of heat shock protein 90 (Hsp90), an adaptor molecule for assembly of endothelial nitric oxide synthase (eNOS) phosphorylation complex. The purpose of this study was to determine whether GGA enhances Hsp90 expression and augments endothelium-dependent vasodilation via upregulation of eNOS in humans.Methods and Results-We evaluated the effects of GGA on human umbilical vein endothelial cells (HUVECs) and on forearm blood flow (FBF) responses to acetylcholine and sodium nitroprusside in 40 healthy young men. Hsp90, eNOS, AMP-activated protein kinase (AMPK), and Akt expression in HUVECs and peripheral blood mononuclear cells was detected by Western blot analysis. GGA increased Hsp90 expression and phosphorylation of eNOS and AMPK but not Akt in HUVECs and increased Hsp90 expression in peripheral blood mononuclear cells. Oral administration of GGA (600 mg) augmented the FBF response to acetylcholine. Infusion of N(G)-monomethyl-L-arginine, an NO synthase inhibitor, completely abolished GGA-induced augmentation of the FBF response to acetylcholine. GGA also augmented the acetylcholine-stimulated NO release in smokers.Conclusion-These findings suggest that GGA-induced activation of Hsp90/AMPK significantly increased NO-mediated vasodilation in healthy subjects, as well as in smokers. The use of GGA may be a new therapeutic approach for improving endothelial dysfunction. (Arterioscler Thromb Vasc Biol. 2012;32:153-160.)