Important Role of Sarcoplasmic Reticulum Ca2+ Release via Ryanodine Receptor-2 Channel in Hypoxia-Induced Rieske Iron-Sulfur Protein-Mediated Mitochondrial Reactive Oxygen Species Generation in Pulmonary Artery Smooth Muscle Cells.
Important Role of Sarcoplasmic Reticulum Ca2+ Release via Ryanodine Receptor-2 Channel in Hypoxia-Induced Rieske Iron-Sulfur Protein-Mediated Mitochondrial Reactive Oxygen Species Generation in Pulmonary Artery Smooth Muscle Cells.
复制标题
肌浆网 Ca2 通过 Ryanodine 受体 2 通道释放在缺氧诱导的 Rieske 铁硫蛋白介导的肺动脉平滑肌细胞线粒体活性氧生成中的重要作用。
DOI：
10.1089/ars.2018.7652
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发表时间：
2020
影响因子：
6.6
通讯作者：
Wang,Yong-Xiao
中科院分区：
文献类型：
--
作者：
Yang,Zhao;Song,Tengyao;Truong,Lillian;Reyes-García,Jorge;Wang,Lan;Zheng,Yun-Min;Wang,Yong-Xiao
目的：众所周知，线粒体活性氧的产生（[ROS]m）会导致肺动脉平滑肌细胞（PASMC）肌浆网（SR）上Ca2+维雅诺定受体2（RyR2）的释放，在缺氧性肺血管收缩（HPV）中发挥重要作用。在本研究中，我们试图确定缺氧诱导的 RyR2 介导的 Ca2+ 释放是否会反过来促进 [ROS]min PASMCs 及其潜在的信号机制。结果：我们的数据表明，应用咖啡因或去甲肾上腺素诱导 Ca2+ 释放会增加 [ROS]min PASMCs。同样，外源 Ca2+ 增强了分离线粒体和 PASMC 复合物 III 中 ROS 的产生。 Ru360 对线粒体 Ca2+ 单向转运蛋白 (MCU) 的抑制可减弱激动剂诱导的 [ROS]m。 Ru360 对缺氧诱导的 [ROS]m 产生类似的抑制作用。 Rieske 铁硫蛋白 (RISP) 基因敲低可抑制 Ca2+- 和咖啡因诱导的 [ROS]m。通过丁卡因或 RyR2 基因敲除抑制 RyR2 可以很好地抑制缺氧诱导的 [ROS]。 创新：在本文中，我们提出了令人信服的证据，表明缺氧或 RyR 模拟后 Ca2+ 释放导致 MCU 显着增加，并且增加的 MCU 随后依赖 RISP 的 [ROS]m，这提供了正反馈机制，以增强缺氧启动的 [ROS]min PASMCs。结论：我们的研究结果表明，缺氧诱导的线粒体ROS 依赖性 SR RyR2 介导的 Ca2+ 释放增加 MCU，然后增加 RISP 依赖性 [ROS]min PASMCs，这可能对 HPV 和相关肺动脉高压做出重大贡献。
Aims:It is known that mitochondrial reactive oxygen species generation ([ROS]m) causes the release of Ca2+viaryanodine receptor-2 (RyR2) on the sarcoplasmic reticulum (SR) in pulmonary artery smooth muscle cells (PASMCs), playing an essential role in hypoxic pulmonary vasoconstriction (HPV). In this study, we sought to determine whether hypoxia-induced RyR2-mediated Ca2+release may in turn promote [ROS]min PASMCs and the underlying signaling mechanism.Results:Our data reveal that application of caffeine or norepinephrine to induce Ca2+release increased [ROS]min PASMCs. Likewise, exogenous Ca2+augmented ROS generation in isolated mitochondria and at complex III from PASMCs. Inhibition of mitochondrial Ca2+uniporter (MCU) with Ru360 attenuated agonist-induced [ROS]m. Ru360 produced a similar inhibitory effect on hypoxia-induced [ROS]m. Rieske iron–sulfur protein (RISP) gene knockdown inhibited Ca2+- and caffeine-induced [ROS]m. Inhibition of RyR2 by tetracaine or RyR2 gene knockout suppressed hypoxia-induced [ROS]mas well.Innovation:In this article, we present convincing evidence that Ca2+release following hypoxia or RyR simulation causes a significant increase in MCU, and the increased MCU subsequently RISP-dependent [ROS]m, which provides a positive feedback mechanism to enhance hypoxia-initiated [ROS]min PASMCs.Conclusion:Our findings demonstrate that hypoxia-induced mitochondrial ROS-dependent SR RyR2-mediated Ca2+release increases MCU and then RISP-dependent [ROS]min PASMCs, which may make significant contributions to HPV and associated pulmonary hypertension.