Differential endothelial hydrogen peroxide signaling via Nox isoforms: Critical roles for Rac1 and modulation by statins.
Differential endothelial hydrogen peroxide signaling via Nox isoforms: Critical roles for Rac1 and modulation by statins.
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DOI：
10.1016/j.redox.2022.102539
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发表时间：
2022-12
期刊：
影响因子：
11.4
通讯作者：
Michel, Thomas
中科院分区：
文献类型：
--
作者：
Waldeck-Weiermair, Markus;Yadav, Shambhu;Kaynert, Jonas;Thulabandu, Venkata Revanth;Pandey, Arvind K.;Spyropoulos, Fotios;Covington, Taylor;Das, Apabrita Ayan;Kruger, Christina;Michel, Thomas
他汀类药物对心血管系统有多种保护作用。除了降低低密度脂蛋白胆固醇水平外，他汀类药物还对心血管组织具有抗氧化作用，涉及细胞内氧化还原途径，但目前尚不完全清楚。他汀类药物抑制HMG-CoA还原酶不仅可以调节胆固醇合成，还可以阻断包括GTPase Rac1在内的信号蛋白翻译后修饰所必需的脂质合成。在这里，我们研究了Rac1和他汀类药物通过NADPH氧化酶（Nox）异构体调节细胞内氧化剂过氧化氢（H2O2）的机制。在使用H2O2生物传感器HyPer7的活细胞成像实验中，我们观察到人脐静脉内皮细胞（HUVEC）在激活细胞表面组胺受体或血管内皮生长因子（VEGF）后产生大量H2O2。VEGF和组胺刺激的H2O2反应都被sirna介导的敲低Rac1所消除。VEGF反应需要Nox亚型Nox2和Nox4，而组胺刺激的H2O2信号不依赖于Nox4，但仍然需要Nox2。辛伐他汀完全抑制了内皮细胞对组胺和VEGF的H2O2反应。在静止的内皮细胞中，Rac1靶向细胞膜和细胞质，但辛伐他汀治疗可促进Rac1易位至细胞核。辛伐他汀对受体依赖性H2O2产生和Rac1易位的影响可以通过用甲羟戊酸处理细胞来恢复，甲羟戊酸是他汀类药物抑制的HMG-CoA还原酶的酶产物。综上所述，这些研究表明，受体调节的H2O2对组胺和VEGF的反应涉及不同的Nox亚型，两者都完全依赖于Rac1戊酰化。该方案说明了他汀类药物的抗氧化作用机制，通过调节Rac1戊烯化，从而破坏组胺和VEGF引发细胞内H2O2生成所需的Rac1/Nox2相互作用。示意图部分改编自Smart Medical Art （https://smart.servier.com/image-set-download/）。施维雅的智能医疗艺术采用知识共享署名3.0未移植许可。内皮细胞胞浆中的HyPer7已被检测到动态受体调节的过氧化氢反应。组胺和vegf诱导的H2O2信号不同地依赖于Nox2和Nox4。依赖nox的H2O2生成需要Rac1。辛伐他汀诱导Rac1易位到细胞核，同时失去激动剂介导的H2O2反应。甲羟戊酸通过恢复Rac1靶向来抵消辛伐他汀治疗。
Statins have manifold protective effects on the cardiovascular system. In addition to lowering LDL cholesterol levels, statins also have antioxidant effects on cardiovascular tissues involving intracellular redox pathways that are incompletely understood. Inhibition of HMG-CoA reductase by statins not only modulates cholesterol synthesis, but also blocks the synthesis of lipids necessary for the post-translational modification of signaling proteins, including the GTPase Rac1. Here we studied the mechanisms whereby Rac1 and statins modulate the intracellular oxidant hydrogen peroxide (H2O2) via NADPH oxidase (Nox) isoforms. In live-cell imaging experiments using the H2O2 biosensor HyPer7, we observed robust H2O2 generation in human umbilical vein endothelial cells (HUVEC) following activation of cell surface receptors for histamine or vascular endothelial growth factor (VEGF). Both VEGF- and histamine-stimulated H2O2 responses were abrogated by siRNA-mediated knockdown of Rac1. VEGF responses required the Nox isoforms Nox2 and Nox4, while histamine-stimulated H2O2 signals are independent of Nox4 but still required Nox2. Endothelial H2O2 responses to both histamine and VEGF were completely inhibited by simvastatin. In resting endothelial cells, Rac1 is targeted to the cell membrane and cytoplasm, but simvastatin treatment promotes translocation of Rac1 to the cell nucleus. The effects of simvastatin both on receptor-dependent H2O2 production and Rac1 translocation are rescued by treatment of cells with mevalonic acid, which is the enzymatic product of the HMG-CoA reductase that is inhibited by statins. Taken together, these studies establish that receptor-modulated H2O2 responses to histamine and VEGF involve distinct Nox isoforms, both of which are completely dependent on Rac1 prenylation. Scheme illustrates the mechanism of the antioxidative effect of statins upon modulating Rac1 prenylation and thereby disrupting the histamine and VEGF elicited Rac1/Nox2 interaction required for cytosolic H2O2 generation. Schematic parts were adapted from Smart Medical Art (https://smart.servier.com/image-set-download/). Smart Medical Art by Servier is licensed under a Creative Commons Attribution 3.0 Unported License. Dynamic receptor-modulated hydrogen peroxide responses have been detected with HyPer7 in the cytosol of endothelial cells. Histamine- and VEGF-induced H2O2 signaling differentially depend on Nox2 and Nox4. Rac1 is required for Nox-dependent H2O2 generation. Simvastatin induces Rac1 translocation to the cell nucleus accompanied with a loss of agonist-mediated H2O2 responses. Mevalonic acid counteracts simvastatin treatment by restoring Rac1 targeting.
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DOI：
10.1083/jcb.200801047
发表时间：
2008-05-05
期刊：
The Journal of cell biology
影响因子：
--
作者：
Michaelson D;Abidi W;Guardavaccaro D;Zhou M;Ahearn I;Pagano M;Philips MR
通讯作者：
Philips MR
影响因子：
11.4
作者：
Bretón-Romero R;Lamas S
通讯作者：
Lamas S
影响因子：
16.6
作者：
Ermakova YG;Bilan DS;Matlashov ME;Mishina NM;Markvicheva KN;Subach OM;Subach FV;Bogeski I;Hoth M;Enikolopov G;Belousov VV
通讯作者：
Belousov VV
影响因子：
120.1
作者：
Drummond, Grant R.;Selemidis, Stavros;Griendling, Kathy K.;Sobey, Christopher G.
通讯作者：
Sobey, Christopher G.
影响因子：
20.1
作者：
Lassègue B;San Martín A;Griendling KK
通讯作者：
Griendling KK