Ammonia promotes endothelial cell survival via the heme oxygenase-1-mediated release of carbon monoxide.
Ammonia promotes endothelial cell survival via the heme oxygenase-1-mediated release of carbon monoxide.
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DOI：
10.1016/j.freeradbiomed.2016.11.029
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发表时间：
2017-01
影响因子：
7.4
通讯作者：
Durante, William
中科院分区：
文献类型：
--
作者：
Liu, Xiao-Ming;Peyton, Kelly J.;Durante, William
尽管内皮细胞在细胞代谢过程中产生大量氨，但这种气体在这些细胞中的生理作用尚不清楚。在这项研究中，我们研究了氨是否调节血红素加氧酶-1 (HO-1) 的表达，以及该酶是否影响氨对内皮细胞的生物作用。外源施用的氨（以氯化铵或氢氧化铵的形式提供）或内源产生的氨刺激培养的人和小鼠内皮细胞中的 HO-1 蛋白表达。膳食补充氨也诱导小鼠动脉中 HO-1 蛋白的表达。氨暴露后 4 小时首次检测到内皮细胞中 HO-1 蛋白因氨而增加，并且与 HO-1 mRNA 的诱导、活性氧 (ROS) 产生的增强以及 NF-E2 相关因子 2 (Nrf2) 表达和活性的增加有关。氨还会激活 HO-1 启动子，但这种情况可以通过抗氧化反应元件突变或过度表达显性失活 Nrf2 来阻断。氨对 HO-1 表达的诱导依赖于 ROS 的形成，并被 N-乙酰半胱氨酸或鱼藤酮阻止。最后，用氨预先处理内皮细胞抑制肿瘤坏死因子-α刺激的细胞死亡。然而，沉默 HO-1 表达会消除氨的保护作用，并且通过施用一氧化碳而非胆红素或铁可以逆转这种保护作用。总之，本研究表明氨通过 ROS-Nrf2 途径刺激内皮细胞中 HO-1 的表达，并且 HO-1 的诱导通过产生一氧化碳有助于氨的细胞保护作用。此外，它还确定氨是脉管系统中潜在的重要信号气体，可促进内皮细胞存活。
Although endothelial cells produce substantial quantities of ammonia during cell metabolism, the physiologic role of this gas in these cells is not known. In this study, we investigated if ammonia regulates the expression of heme oxygenase-1 (HO-1), and if this enzyme influences the biological actions of ammonia on endothelial cells. Exogenously administered ammonia, given as ammonium chloride or ammonium hydroxide, or endogenously generated ammonia stimulated HO-1 protein expression in cultured human and murine endothelial cells. Dietary supplementation of ammonia also induced HO-1 protein expression in murine arteries. The increase in HO-1 protein by ammonia in endothelial cells was first detected 4 hours after ammonia exposure and was associated with the induction of HO-1 mRNA, enhanced production of reactive oxygen species (ROS), and increased expression and activity of NF-E2-related factor-2 (Nrf2). Ammonia also activated the HO-1 promoter and this was blocked by mutating the antioxidant responsive element or by overexpressing dominant-negative Nrf2. The induction of HO-1 expression by ammonia was dependent on ROS formation and prevented by N-acetylcysteine or rotenone. Finally, prior treatment of endothelial cells with ammonia inhibited tumor necrosis factor-α -stimulated cell death. However, silencing HO-1 expression abrogated the protective action of ammonia and this was reversed by the administration of carbon monoxide but not bilirubin or iron. In conclusion, this study demonstrates that ammonia stimulates the expression of HO-1 in endothelial cells via the ROS-Nrf2 pathway, and that the induction of HO-1 contributes to the cytoprotective action of ammonia by generating carbon monoxide. Moreover, it identifies ammonia as a potentially important signaling gas in the vasculature that promotes endothelial cell survival.
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影响因子：
20.1
作者：
Calvert JW;Jha S;Gundewar S;Elrod JW;Ramachandran A;Pattillo CB;Kevil CG;Lefer DJ
通讯作者：
Lefer DJ
影响因子：
64.5
作者：
De Bock, Katrien;Georgiadou, Maria;Carmeliet, Peter
通讯作者：
Carmeliet, Peter
DOI：
10.1111/j.1748-1716.1981.tb06906.x
发表时间：
1981-01-01
期刊：
ACTA PHYSIOLOGICA SCANDINAVICA
影响因子：
--
作者：
ANDERSSON, KE;BRANDT, L;LJUNGGREN, B
通讯作者：
LJUNGGREN, B
影响因子：
3.2
作者：
Durante W
通讯作者：
Durante W
影响因子：
13.5
作者：
Chen, Feng;Ohashi, Norifumi;Li, Wensheng;Eckman, Christopher;Nguyen, Justin H.
通讯作者：
Nguyen, Justin H.