Ginkgo biloba extract attenuates oxLDL-induced endothelial dysfunction via an AMPK-dependent mechanism
Ginkgo biloba extract attenuates oxLDL-induced endothelial dysfunction via an AMPK-dependent mechanism
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DOI：
10.1152/japplphysiol.00367.2012
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发表时间：
2013-01-01
影响因子：
3.3
通讯作者：
Lee, Shin-Da
中科院分区：
文献类型：
--
作者：
Ou, Hsiu-Chung;Hsieh, Yueh-Ling;Lee, Shin-Da
银杏叶提取物通过AMPK依赖性机制减轻oxLDL诱导的内皮功能障碍J Appl Physiol 114：274-285，2013.首次发表于2012年11月29日; doi：10.1152/japplphysiol.00367.2012.-动脉粥样硬化是一种复杂的炎症性动脉疾病，氧化低密度脂蛋白（oxLDL）与慢性血管炎症直接相关。以前的研究表明，银杏叶提取物（GbE）作为神经和心血管疾病的治疗剂。然而，介导GbE作用的机制在很大程度上仍然未知。在本研究中，我们测试的假设，GbE保护oxLDL诱导的内皮功能障碍，通过AMP激活的蛋白激酶（AMPK）依赖性机制。人脐静脉内皮细胞用GbE处理，然后用oxLDL处理指定的时间段。Western blot结果显示，GbE可抑制oxLDL诱导的AMPK去磷酸化及随后的PKC激活引起的NADPH氧化酶亚基p47（phox）和Rac-1的膜转位，并减弱膜亚基gp 91和p22（phox）蛋白表达的增加。AMPK-α（1）特异性小干扰RNA转染细胞暴露于GbE，然后暴露于oxLDL，显示PKC和p47（phox）水平升高。此外，暴露于oxLDL导致AMPK介导的Akt/内皮一氧化氮（NO）合酶信号传导减少，并诱导p38丝裂原活化蛋白激酶磷酸化，进而激活NF-κ B介导的炎症反应，如白细胞介素-8的释放、粘附分子的表达以及单核细胞与人脐静脉内皮细胞的粘附。此外，oxLDL上调诱导型NO合酶的表达，从而增加NO的形成和蛋白质亚硝基化。然而，GbE预处理以剂量依赖的方式产生显著的细胞保护作用。这项研究的结果可能会提供有关GbE保护oxLDL诱导的内皮功能障碍的可能分子机制的见解。
Ginkgo biloba extract attenuates oxLDL-induced endothelial dysfunction via an AMPK-dependent mechanism. J Appl Physiol 114: 274-285, 2013. First published November 29, 2012; doi:10.1152/japplphysiol.00367.2012.-Atherosclerosis is a complex inflammatory arterial disease, and oxidized low-density lipoprotein (oxLDL) is directly associated with chronic vascular inflammation. Previous studies have shown that Ginkgo biloba extract (GbE) acts as a therapeutic agent for neurological and cardiovascular disorders. However, the mechanisms mediating the actions of GbE are still largely unknown. In the present study, we tested the hypothesis that GbE protects against oxLDL-induced endothelial dysfunction via an AMP-activated protein kinase (AMPK)-dependent mechanism. Human umbilical vein endothelial cells were treated with GbE, followed by oxLDL, for indicated time periods. Results from Western blot showed that GbE inhibited the membrane translocation of the NADPH oxidase subunits p47(phox) and Rac-1 and attenuated the increase in protein expression of membrane subunits gp91 and p22(phox) caused by oxLDL-induced AMPK dephosphorylation and subsequent PKC activation. AMPK-alpha(1)-specific small interfering RNA-transfected cells that had been exposed to GbE followed by oxLDL revealed elevated levels of PKC and p47(phox). In addition, exposure to oxLDL resulted in reduced AMPK-mediated Akt/endothelial nitric oxide (NO) synthase signaling and the induction of phosphorylation of p38 mitogen-activated protein kinase, which, in turn, activated NF-kappa B-mediated inflammatory responses, such as the release of interleukin-8, the expression of the adhesion molecule, and the adherence of monocytic cells to human umbilical vein endothelial cells. Furthermore, oxLDL upregulated the expression of inducible NO synthase, thereby augmenting the formation of NO and protein nitrosylation. Pretreatment with GbE, however, exerted significant cytoprotective effects in a dose-dependent manner. Results from this study may provide insight into a possible molecular mechanism by which GbE protects against oxLDL-induced endothelial dysfunction.