Homocysteine Causes Endothelial Dysfunction via Inflammatory Factor-Mediated Activation of Epithelial Sodium Channel (ENaC).
Homocysteine Causes Endothelial Dysfunction via Inflammatory Factor-Mediated Activation of Epithelial Sodium Channel (ENaC).
复制标题
同型半胱氨酸通过炎症因子介导的上皮钠通道 (ENaC) 激活导致内皮功能障碍
DOI：
10.3389/fcell.2021.672335
复制
发表时间：
2021
影响因子：
5.5
通讯作者：
Zhang ZR
中科院分区：
文献类型：
--
作者：
Liang C;Wang QS;Yang X;Zhu D;Sun Y;Niu N;Yao J;Dong BH;Jiang S;Tang LL;Lou J;Yu CJ;Shao Q;Wu MM;Zhang ZR
高同型半胱氨酸血症（Hyperhomocysteinemia，HHcy）通过调节炎症反应而引起心血管疾病。我们研究了上皮钠通道（ENaC），最近确定的离子通道在内皮细胞，是否以及如何发挥作用，在HHcy诱导的内皮功能障碍。采用细胞贴附膜片钳技术、蛋白质印迹、共聚焦成像和钢丝肌电描记术结合药理学方法来确定HHcy介导的炎症信号是否通过刺激ENaC导致内皮功能障碍。实验结果表明，L-蛋氨酸饲料喂养4周后，小鼠血浆Hcy水平显著升高，主动脉内皮细胞ENaC显著激活。苯扎明，一个特定的ENaC阻断剂，管理，改善L-蛋氨酸饮食诱导的内皮依赖性舒张功能（EDR）的损害和逆转Hcy诱导的ENaC活性的增加。NADPH氧化酶、活性氧（ROS）、环氧合酶-2（考克斯-2）/血栓素B2（TXB 2）或血清/糖皮质激素调节激酶1（SGK 1）的药理学抑制有效地减弱了Hcy诱导的内皮ENaC活化和EDR损伤。我们的体外实验数据显示，NADPH氧化酶抑制剂和ROS清除剂均可逆转Hcy诱导的人脐静脉内皮细胞（HUVECs）中考克斯-2表达的增加。此外，Hcy诱导的SGK-1、磷酸化SGK-1和磷酸化神经前体细胞表达的发育下调蛋白4-2（p-Nedd 4 -2）在HUVEC中表达水平的增加被考克斯-2抑制剂显著减弱。我们发现，同型半胱氨酸激活内皮ENaC，随后损害小鼠主动脉的EDR，通过ROS/考克斯-2依赖性激活SGK-1/Nedd 4 -2信号。我们的研究为阻断内皮ENaC可能成为预防和/或治疗Hcy诱导的心血管疾病的潜在方法提供了理论依据。
Hyperhomocysteinemia (HHcy) causes cardiovascular diseases via regulating inflammatory responses. We investigated whether and how the epithelial sodium channel (ENaC), a recently identified ion channel in endothelial cells, plays a role in HHcy-induced endothelial dysfunction. Cell-attached patch-clamp recording in acute split-open aortic endothelial cells, western blot, confocal imaging, and wire myograph combined with pharmacological approaches were used to determine whether HHcy-mediated inflammatory signaling leads to endothelial dysfunction via stimulating ENaC. The data showed that 4 weeks after L-methionine diet the levels of plasma Hcy were significantly increased and the ENaC was dramatically activated in mouse aortic endothelial cells. Administration of benzamil, a specific ENaC blocker, ameliorated L-methionine diet-induced impairment of endothelium-dependent relaxation (EDR) and reversed Hcy-induced increase in ENaC activity. Pharmacological inhibition of NADPH oxidase, reactive oxygen species (ROS), cyclooxygenase-2 (COX-2)/thromboxane B2 (TXB2), or serum/glucocorticoid regulated kinase 1 (SGK1) effectively attenuated both the Hcy-induced activation of endothelial ENaC and impairment of EDR. Our in vitro data showed that both NADPH oxidase inhibitor and an ROS scavenger reversed Hcy-induced increase in COX-2 expression in human umbilical vein endothelial cells (HUVECs). Moreover, Hcy-induced increase in expression levels of SGK-1, phosphorylated-SGK-1, and phosphorylated neural precursor cell-expressed developmentally downregulated protein 4-2 (p-Nedd4-2) in HUVECs were significantly blunted by a COX-2 inhibitor. We show that Hcy activates endothelial ENaC and subsequently impairs EDR of mouse aorta, via ROS/COX-2-dependent activation of SGK-1/Nedd4-2 signaling. Our study provides a rational that blockade of the endothelial ENaC could be potential method to prevent and/or to treat Hcy-induced cardiovascular disease.
登录
查看更多内容
影响因子：
5.4
作者：
Ganguly P;Alam SF
通讯作者：
Alam SF
Nox4和可溶性环氧化物水解酶协同介导同型半胱氨酸诱导的血管平滑肌细胞炎症
影响因子：
4
作者：
Liu, Xi;Qin, Zhexue;Huang, Lan
通讯作者：
Huang, Lan
DOI：
10.1161/01.atv.0000189559.87328.e4
发表时间：
2005-12-01
影响因子：
8.7
作者：
Jiang, XH;Yang, F;Wang, H
通讯作者：
Wang, H
影响因子：
7.3
作者：
Shi, Y.;Vanhoutte, P. M.
通讯作者：
Vanhoutte, P. M.
影响因子：
11.4
作者：
Ma CH;Chiua YC;Wu CH;Jou IM;Tu YK;Hung CH;Hsieh PL;Tsai KL
通讯作者：
Tsai KL