S-亞硝基穀胱甘肽(GSNO)介導大腦對缺氧的反應(S-Nitrosoglutathione (GSNO) Mediates Brain Response to Hypoxia)


S-亞硝基穀胱甘肽(GSNO)介導大腦對缺氧的反應

評論:Lipton AJ,Johnson MA,Macdonald T,et al。 2001 S-亞硝基硫醇表示對缺氧的通氣反應。自然413:171-174

一氧化氮(NO)氣體是通常在內燃機中形成的活性氮物質。在生物系統中,它由L-精氨酸通過神經元(NOS1),巨噬細胞(NOS2)和內皮(NOS3)中的三種一氧化氮合酶同工型合成。除誘導型NOS2外,神經元NOS1和內皮NOS3也可誘導和反饋調節。乙酰膽鹼激活心血管系統中的內皮NOS3導致NO釋放或內皮衍生的鬆弛因子(EDRF)隨後進入血管平滑肌引發血管舒張(1998年諾貝爾獎RF Furchgott,LJ Ignarro和F的項目) .Murad)通過循環GMP(cGMP)依賴機制(1)。由於氮原子上高反應性不成對電子的自由基特性,NO具有化學反應性和生物多功能性(2)。最近,美國和歐盟批准了藥用NO氣體作為持續性肺動脈高壓的治療方法。由NicOx S.A.開發的一些新的NO供體試劑(即NCX 1015)正在進行臨床試驗。

NO的主要化學和生物學效應非常有趣(2)。 1)NO與血紅素部分結合以活化鳥苷酸環化酶以通過cGMP-PKG途徑發信號以誘導血管舒張和神經保護。 2)NO還與鐵結合併調節鐵絡合物的氧化還原循環,包括血紅蛋白,鐵調節蛋白和檸檬酸亞鐵。 3)NO是非典型抗氧化劑而不是促氧化劑,因為它清除細胞毒活性氧物質和過氧化脂質基團。 4)NO是含半胱氨酸的肽(即L-穀胱甘肽/γ-GSH)的氧化還原調節劑,因為它容易與半胱氨酸的巰基(-SH)反應形成S-亞硝基半胱氨酸和/或巰基(ĠS) GSH分別形成S-亞硝基穀胱甘肽(GSNO)。在藥理學上,吸入NO氣體可增加氣道肌肉鬆弛。肺中的一些吸入和/或誘導的NO可轉化為GSNO和其他S-亞硝基硫醇,其阻止血小板聚集,促進對氧的攝取和遞送的控制,並調節N-甲基-d-天冬氨酸(NMDA)離子頻道(3,4)。此外,GSNO對過氧亞硝酸鹽(ONOO-)引起的氧化應激的作用比GSH強至少3至5個數量級(5)。 GSNO激活cGMP介導的硫氧還蛋白(TRX)合成,其保護免受氧化應激誘導的細胞凋亡,從而促進預處理誘導的代償性激素或神經保護作用(6)。

在中樞神經系統中,在1)內皮細胞和2)星形膠質細胞的缺血期間可以產生GSNO,其中發現微摩爾水平的NO和毫摩爾濃度的GSH(7)。 GSNO在生物系統中比其前體NO更穩定;它可以進入鄰近的神經元並被γ-谷氨酰轉肽酶(γ-GT)轉化為S-亞硝基半胱氨酰甘氨酸(CGSNO)。 CGSNO是推定的信號分子,用於調節孤束核(NTS)腦乾水平的缺氧通氣反應(8)和控制丘腦腹側感覺傳遞(9)。 Lipton等人。 (8)採用質譜法顯示,當注入NTS時,從脫氧但未充氧的血液中獲得的GSNO模擬缺氧的通氣作用。 Salt等人領導的研究小組報告了腦區CGSNO的產生。 (9)。基因敲除或acivicin對γ-GT的抑制都會阻止GSNO在NTS中的生理作用。這些體內研究結果表明,CGSNO是腦幹中的一種信號分子,用於觸發缺氧後肺通氣的cGMP非依賴性反饋調節。 Lipton等人的這些優雅結果。 (8)與Chiueh和Rauhala(7)最近的提議相吻合,即GSNO和相關的S-亞硝基硫醇可以作為內皮細胞或星形膠質細胞與腦神經元之間的信號分子。本文在最近的評論(10)中增加了觀察結果,並一起強調並解釋了這些發現的重要性。 Lipton等人的研究和之前的S-亞硝基硫醇研究將被生理學和藥理學教科書引用作為關鍵觀察結果,這些觀察結果促進了我們對GSNO和相關CGSNO在腦功能中的關鍵信號傳導作用的理解,尤其是細胞與神經元通信的控製作用。呼吸週期。


原文


A review of: Lipton AJ, Johnson MA, Macdonald T, et al. 2001 S-nitrosothiols signal the ventilatory response to hypoxia. Nature 413:171–174

Nitric oxide (NO) gas is a reactive nitrogen species routinely formed in combustion engines. In biological systems, it is synthesized from l-arginine by three isoforms of nitric oxide synthase in neurons (NOS1), macrophages (NOS2), and endothelium (NOS3). In addition to inducible NOS2, neuronal NOS1 and endothelial NOS3 are also inducible and feedback regulated. The activation of endothelial NOS3 in the cardiovascular system by acetylcholine leads to the release of NO or the endothelium-derived relaxing factor (EDRF) that subsequently enters vascular smooth muscle triggering vasorelaxation (the 1998 Nobel Prize project of R.F. Furchgott, L.J. Ignarro, and F. Murad) via a cyclic GMP (cGMP)-dependent mechanism (1). Owing to the free radical property of the highly reactive unpaired electron on the nitrogen atom, NO is chemically reactive and biologically multifunctional (2). Medicinal NO gas has been recently approved as a treatment of persistent pulmonary hypertension in the United States and the European Union. Some of the new NO donor agents (ie NCX 1015)developed by the NicOx S.A. are undergoing clinical trials.

The major chemical and biological effects of NO are very intriguing (2). 1) NO binds to the heme moiety to activate guanylyl cyclase for signaling through the cGMP-PKG pathway to induce vasorelaxation and neuroprotection. 2) NO also binds to iron and regulates the redox cycling of iron complexes including hemoglobin, iron regulating protein, and ferrous citrate. 3) NO is an atypical antioxidant rather than a pro-oxidant since it scavenges cytotoxic reactive oxygen species and peroxyl lipid radicals. 4) NO is a redox modulator for cysteine-containing peptides (ie L-glutathione/γ-GSH) because it readily reacts with the sulfhydryl group (-SH) of cysteine to form S-nitrosocysteine and/or thiol radical (ĠS) of GSH to form S-nitrosoglutathione (GSNO), respectively. Pharmacologically, inhalation of NO gas increases airway muscle relaxation. Some of the inhaled and/or induced NO in the lung may convert to GSNO and other S-nitrosothiols that prevent platelet aggregation, facilitate the control of uptake and delivery of oxygen, and regulate the N-methyl-d-aspartate (NMDA) ion channel (3,4). Furthermore, GSNO is at least 3 to 5 orders of magnitude more potent than GSH against oxidative stress caused by peroxynitrite (ONOO−) (5). GSNO activates a cGMP-mediated synthesis of thioredoxin (TRX) that protects against oxidative stress-induced apoptosis for promoting preconditioning-induced compensatory hormesis or neuroprotection (6).

In the central nervous system GSNO can be generated during ischemia in 1) endothelial and 2) astroglial cells where micromolar levels of NO and millimolar concentrations of GSH are found (7). GSNO is more stable in the biological system than its precursor NO; it can enter neighboring neurons and be converted by γ-glutamyl transpeptidase (γ-GT) to S-nitrosocysteinyl glycine (CGSNO). CGSNO is the putative signaling molecule for regulating the ventilatory responses to hypoxia at the brain stem level of the nuclear tractus solitarius (NTS) (8) and for controlling sensory transmission in the ventrobasal thalamus (9). Lipton et al. (8) employed mass spectrometry to show that GSNO obtained from deoxygenated, but not oxygenated, blood when infused into NTS mimics the ventilatory effects of hypoxia. The generation of CGSNO in the brain regions has been reported by the research team leaded by Salt et al. (9). Either gene knockout or inhibition of γ-GT by acivicin prevents the physiological effects of GSNO in the NTS. These in vivo findings indicate that CGSNO is a signaling molecule in the brain stem for triggering a cGMP-independent feedback regulation of ventilation in the lung following hypoxia. These elegant results of Lipton et al. (8) fit well with a recent proposal of Chiueh and Rauhala (7) that GSNO and related S-nitrosothiols may serve as signaling molecules between endothelial or astroglial cells and brain neurons. The present article adds to the observations in a recent commentary (10) and together emphasizes and explains the importance of these findings. The studies of Lipton et al and prior S-nitrosothiol studies will be cited by physiology and pharmacology textbooks as key observations that advance our understanding of the pivotal signaling role of GSNO and related CGSNO in brain function, especially the cell to neuron communication for controlling the respiratory cycle.

#GSNO #天然誓約
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