Activation of thromboxane A2 receptors mediates endothelial dysfunction in diabetic mice
Activation of thromboxane A2 receptors mediates endothelial dysfunction in diabetic mice
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血栓素 A2 受体激活介导糖尿病小鼠内皮功能障碍
DOI：
10.1080/10641963.2016.1246558
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发表时间：
2017-05
影响因子：
12.3
通讯作者：
Liu Ning
中科院分区：
文献类型：
--
作者：
Xie Xiaona;Sun Wanchun;Wang Jun;Li Xiaoou;Liu Xiaofeng;Liu Ning
背景：糖尿病是心血管疾病的高危因素之一。改善糖尿病内皮功能障碍可减少血管并发症。然而，底层机制需要to.be来揭示。本研究旨在阐明血栓素A2受体（TPr）激活是否以及如何参与糖尿病内皮功能障碍。方法和结果：人脐静脉内皮细胞（HUVECs）暴露于TPr激动剂，两种结构相关的血栓素A2。（TxA 2）模拟物，显着减少内皮型一氧化氮合酶（eNOS）的磷酸化在Ser 1177和Akt在Ser 473。这些作用被TPr的药理学或遗传抑制剂所消除。TPR诱导的eNOS和Akt磷酸化的抑制伴随着PTEN的上调。（在染色体10上缺失的磷酸酶和张力同源物）和Ser 380/Thr 382/383 PTEN磷酸化。PTEN特异性siRNA在TPr激活的情况下恢复了Akt-eNOS信号传导。TPr刺激也可激活小的GT3-Rho，用Rho相关激酶（ROCK）抑制剂Y27632预处理HUVECs可挽救TPr损伤的Akt-eNOS信号。在小鼠中，链脲佐菌素诱导的糖尿病与主动脉PTEN上调、PTEN-Ser 380/Thr 382/383磷酸化以及Akt（Ser 473）和eNOS（Ser 1177）的去磷酸化有关。重要的是，TPr拮抗剂的施用阻断了这些变化。结论：TPr激活可通过选择性地抑制ROCK-PTEN-Akt-eNOS通路而损害糖尿病小鼠的内皮功能。
Background: Diabetes is one of high-risk factors for cardiovascular disease. Improvement of endothelial.dysfunction in diabetes reduces vascular complications. However, the underlying mechanism needs to.be uncovered. This study was conducted to elucidate whether and how thromboxane A2 receptor (TPr).activation contributes to endothelial dysfunction in diabetes. Methods and Results: Exposure of human.umbilical vein endothelial cells (HUVECs) to either TPr agonists, two structurally related thromboxane A2.(TxA2) mimetics, significantly reduced phosphorylations of endothelial nitric oxide synthase (eNOS) at.Ser1177 and Akt at Ser473. These effects were abolished by pharmacological or genetic inhibitors of TPr..TPr-induced suppression of eNOS and Akt phosphorylation was accompanied by upregulation of PTEN.(phosphatase and tension homolog deleted on chromosome 10) and Ser380/Thr382/383 PTEN phosphorylation..PTEN-specific siRNA restored Akt–eNOS signaling in the face of TPr activation. The small GTPase,.Rho, was also activated by TPr stimulation, and pretreatment of HUVECs with Y27632, a Rho-associated.kinase (ROCK) inhibitor, rescued TPr-impaired Akt–eNOS signaling. In mice, streptozotocin-induced.diabetes was associated with aortic PTEN upregulation, PTEN-Ser380/Thr382/383 phosphorylation, and.dephosphorylation of Akt (at Ser473) and eNOS (at Ser1177). Importantly, administration of TPr antagonist.blocked these changes. Conclusion: We conclude that TPr activation impairs endothelial function by.selectively inactivating the ROCK–PTEN–Akt–eNOS pathway in diabetic mice.
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影响因子：
15.9
作者：
Kobayashi, T;Tahara, Y;Narumiya, S
通讯作者：
Narumiya, S
影响因子：
20.1
作者：
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通讯作者：
Zou MH
影响因子：
7.7
作者：
Wang S;Xu J;Song P;Viollet B;Zou MH
通讯作者：
Zou MH
影响因子：
7.7
作者：
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T. Utsugi;J. Yoon;Byung-Ju Park;M. Imamura;N. Averill;S. Kawazu;P. Santamaria
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影响因子：
5.3
作者：
Yang XH;Li P;Yin YL;Tu JH;Dai W;Liu LY;Wang SX
通讯作者：
Wang SX