Angiotensin II Decreases Endothelial Nitric Oxide Synthase Phosphorylation via AT(1)R Nox/ROS/PP2A Pathway.
Angiotensin II Decreases Endothelial Nitric Oxide Synthase Phosphorylation via AT(1)R Nox/ROS/PP2A Pathway.
复制标题
DOI：
10.3389/fphys.2020.566410
复制
发表时间：
2020
影响因子：
4
通讯作者：
Lu D
中科院分区：
文献类型：
--
作者：
Ding J;Yu M;Jiang J;Luo Y;Zhang Q;Wang S;Yang F;Wang A;Wang L;Zhuang M;Wu S;Zhang Q;Xia Y;Lu D
越来越多的证据表明，血管紧张素（Ang）II通过多种信号通路参与内皮功能障碍（艾德）的发病，包括血管紧张素1型受体（AT 1 R）介导的NADPH氧化酶（Nox）/活性氧（ROS）信号转导。然而，详细的机制并不完全清楚。在本研究中，我们报道了AngII/AT 1 R介导的活化蛋白磷酸酶2A（PP 2A）通过Nox/ROS途径下调内皮型一氧化氮合酶（eNOS）磷酸化。AngII处理可降低eNOS Ser 1177磷酸化水平和一氧化氮（NO）含量沿着降低PP 2Ac（PP 2A催化亚基）Tyr 307磷酸化水平，同时增加PP 2A活性和ROS产生。AT 1 R拮抗剂坎地沙坦（CAN）可阻断上述变化。10−8 M PP 2A抑制剂冈田酸（OA）的预处理逆转了eNOS Ser 1177和NO含量的水平。AngII对PP 2A和eNOS的类似作用也在通过渗透微泵输注AngII 2周的Sprague-Dawley大鼠的肠系膜动脉中观察到。结果表明，在肠系膜动脉中，PP 2A活性升高，而PP 2AcTyr 307和eNOS Ser 1177水平以及NO含量降低。抗氧化剂N-乙酰半胱氨酸（NAC）和夹竹桃素（APO）预处理可阻断Ang Ⅱ诱导的HUVECs内PP 2Ac Tyr 307和eNOS Ser 1177水平的下降。小分子干扰RNA（siRNA）敲低p22 phox后，ROS产生减少，PP 2Ac Tyr 307和eNOS Ser 1177水平升高。这些结果表明，AngII/AT 1 R途径通过下调其催化亚基Tyr 307磷酸化来激活PP 2A，该亚基依赖于Nox激活和ROS产生。总之，我们的研究结果表明，AngII下调PP 2A催化亚基Tyr 307磷酸化，通过AT 1 R介导的Nox/ROS信号通路激活PP 2A。激活的PP 2A进一步降低eNOS Ser 1177磷酸化水平和NO含量，导致内皮功能障碍。
Increasing evidences suggest that angiotensin (Ang) II participates in the pathogenesis of endothelial dysfunction (ED) through multiple signaling pathways, including angiotensin type 1 receptor (AT1R) mediated NADPH oxidase (Nox)/reactive oxygen species (ROS) signal transduction. However, the detailed mechanism is not completely understood. In this study, we reported that AngII/AT1R-mediated activated protein phosphatase 2A (PP2A) downregulated endothelial nitric oxide synthase (eNOS) phosphorylation via Nox/ROS pathway. AngII treatment reduced the levels of phosphorylation of eNOS Ser1177 and nitric oxide (NO) content along with phosphorylation of PP2Ac (PP2A catalytic subunit) Tyr307, meanwhile increased the PP2A activity and ROS production in human umbilical vein endothelial cells (HUVECs). These changes could be impeded by AT1R antagonist candesartan (CAN). The pretreatment of 10−8 M PP2A inhibitor okadaic acid (OA) reversed the levels of eNOS Ser1177 and NO content. Similar effects of AngII on PP2A and eNOS were also observed in the mesenteric arteries of Sprague-Dawley rats subjected to AngII infusion via osmotic minipumps for 2 weeks. We found that the PP2A activity was increased, but the levels of PP2Ac Tyr307 and eNOS Ser1177 as well as NO content were decreased in the mesenteric arteries. The pretreatments of antioxidant N-acetylcysteine (NAC) and apocynin (APO) abolished the drop of the levels of PP2Ac Tyr307 and eNOS Ser1177 induced by AngII in HUVECs. The knockdown of p22phox by small interfering RNA (siRNA) gave rise to decrement of ROS production and increment of the levels of PP2Ac Tyr307 and eNOS Ser1177. These results indicated that AngII/AT1R pathway activated PP2A by downregulating its catalytic subunit Tyr307 phosphorylation, which relies on the Nox activation and ROS production. In summary, our findings indicate that AngII downregulates PP2A catalytic subunit Tyr307 phosphorylation to activate PP2A via AT1R-mediated Nox/ROS signaling pathway. The activated PP2A further decreases levels of eNOS Ser1177 phosphorylation and NO content leading to endothelial dysfunction.
登录
查看更多内容
DOI：
10.1152/ajplung.00261.2012
发表时间：
2013-03-01
影响因子：
4.9
作者：
Menden, Heather;Tate, Everett;Sampath, Venkatesh
通讯作者：
Sampath, Venkatesh
DOI：
10.1007/978-1-62703-562-0_17
发表时间：
2013-01-01
期刊：
PHOSPHATASE MODULATORS
影响因子：
--
作者：
Lambrecht, Caroline;Haesen, Dorien;Janssens, Veerle
通讯作者：
Janssens, Veerle
影响因子：
4.5
作者：
Fleming, Ingrid
通讯作者：
Fleming, Ingrid
影响因子：
3.3
作者：
Aldini, Giancarlo;Altomare, Alessandra;Sergio, Francesco
通讯作者：
Sergio, Francesco
影响因子：
14.5
作者：
BRAUTIGAN, DL
通讯作者：
BRAUTIGAN, DL