VDR Agonist Prevents Diabetic Endothelial Dysfunction through Inhibition of Prolyl Isomerase-1-Mediated Mitochondrial Oxidative Stress and Inflammation.
VDR Agonist Prevents Diabetic Endothelial Dysfunction through Inhibition of Prolyl Isomerase-1-Mediated Mitochondrial Oxidative Stress and Inflammation.
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VDR 激动剂通过抑制脯氨酰异构酶 1 介导的线粒体氧化应激和炎症来预防糖尿病内皮功能障碍
DOI：
10.1155/2018/1714896
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发表时间：
2018
影响因子：
--
通讯作者：
Lin J
中科院分区：
文献类型：
--
作者：
Zhang M;Lin L;Xu C;Chai D;Peng F;Lin J
脯氨酸异构酶-1 （Pin1）蛋白表达和活性的上调通过诱导内皮氧化应激和炎症与糖尿病血管病变的发病机制有关。此外，VDR激动剂通过抑制氧化应激来防止高糖诱导的内皮细胞凋亡。我们的目的是探讨VDR激动剂对糖尿病相关内皮功能障碍的影响以及Pin1在这一过程中的作用。链脲佐菌素诱导的糖尿病小鼠随机给予载药、VDR激动剂（10 μg/kg/d, ig，每周2次）或Pin1抑制剂Juglone （1 mg/kg/d, ig，每隔2天），连续8周。同时，将暴露于高糖条件下的人脐静脉内皮细胞（HUVECs）用1,25-二羟基维生素D3和Juglone或对照剂处理72小时。器官室实验评估乙酰胆碱的内皮依赖性松弛。检测糖尿病小鼠外周血中Pin1、SOD、MDA、IL-1β、IL-6、NO水平，以及高糖培养huvec中Pin1蛋白的表达和活性、p66Shc和NF-κB p65的亚细胞分布。VDR激动剂和Juglone均可显著改善糖尿病相关的内皮功能障碍，减少高糖诱导的内皮细胞凋亡。机制上，与糖尿病小鼠相比，血液中SOD和NO水平升高。此外，VDR激动剂和Juglone还能抑制高糖培养huvec中Pin1蛋白的表达和活性、p66Shc线粒体易位和NF-κB p65。敲低VDR可消除VDR激动剂对高糖诱导的Pin1蛋白表达和活性上调的抑制作用。VDR激动剂通过抑制pin1介导的线粒体氧化应激和炎症来预防糖尿病内皮功能障碍。
Upregulation of prolyl isomerase-1 (Pin1) protein expression and activity was associated with the pathogenesis of diabetic vasculopathy through induction of endothelial oxidative stress and inflammation. Moreover, VDR agonist protects against high glucose-induced endothelial apoptosis through the inhibition of oxidative stress. We aimed to explore the effects of the VDR agonist on diabetes-associated endothelial dysfunction and the role of Pin1 in this process. Streptozocin-induced diabetic mice were randomly treated with vehicle, VDR agonist (10 μg/kg/d, i.g., twice a week), or Pin1 inhibitor, Juglone (1 mg/kg/d, i.p., every other day), for eight weeks. In parallel, human umbilical vein endothelial cells (HUVECs) exposed to high-glucose condition were treated with 1,25-dihydroxyvitamin D3 and Juglone or vehicle for 72 hours. Organ chamber experiments were performed to assess endothelium-dependent relaxation to acetylcholine. Circulatory levels of Pin1, SOD, MDA, IL-1β, IL-6, and NO in diabetic mice, Pin1 protein expression and activity, subcellular distribution of p66Shc, and NF-κB p65 in high glucose-cultured HUVECs were determined. Both VDR agonist and Juglone significantly improved diabetes-associated endothelial dysfunction and reduced high glucose-induced endothelial apoptosis. Mechanistically, the circulatory levels of SOD and NO were increased compared with those of vehicle-treated diabetic mice. Additionally, Pin1 protein expression and activity, p66Shc mitochondrial translocation, and NF-κB p65 in high glucose-cultured HUVECs were also inhibited by VDR agonist and Juglone. Knockdown of VDR abolished the inhibitory effects of VDR agonist on high glucose-induced upregulation of Pin1 protein expression and activity. VDR agonist prevents diabetic endothelial dysfunction through inhibition of Pin1-mediated mitochondrial oxidative stress and inflammation.
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影响因子：
4.2
作者：
Grupper, Ayelet;Shashar, Moshe;Schwartz, Idit F.
通讯作者：
Schwartz, Idit F.
影响因子：
39.3
作者：
Paneni F;Beckman JA;Creager MA;Cosentino F
通讯作者：
Cosentino F
影响因子：
--
作者：
Afanas'ev I
通讯作者：
Afanas'ev I
影响因子：
--
作者：
Magenta A;Greco S;Capogrossi MC;Gaetano C;Martelli F
通讯作者：
Martelli F
影响因子：
39.3
作者：
Paneni, Francesco;Costantino, Sarah;Cosentino, Francesco
通讯作者：
Cosentino, Francesco