Acyloxy nitroso compounds inhibit LIF signaling in endothelial cells and cardiac myocytes: evidence that STAT3 signaling is redox-sensitive.
Acyloxy nitroso compounds inhibit LIF signaling in endothelial cells and cardiac myocytes: evidence that STAT3 signaling is redox-sensitive.
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DOI：
10.1371/journal.pone.0043313
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Booz GW
中科院分区：
文献类型：
--
作者：
Zgheib C;Kurdi M;Zouein FA;Gunter BW;Stanley BA;Zgheib J;Romero DG;King SB;Paolocci N;Booz GW
我们之前发现氧化应激通过靶向JAK1抑制白血病抑制因子（LIF）信号，并且JAK1和jak2的催化结构域具有基于半胱氨酸的氧化还原开关。因此，我们假设NO的兄弟化合物和硫代化合物硝基（HNO）会抑制liff诱导的JAK-STAT3激活。人微血管内皮细胞（HMEC-1）或新生大鼠心肌细胞用HNO供体Angeli 's盐或亚硝基环己酯醋酸酯（NCA）预处理，可抑制lif诱导的STAT3活化。NCA预处理还阻断了下游炎症基因的诱导（如细胞间粘附分子1、CCAAT/增强子结合蛋白δ）。相关的1-亚硝基环己基戊酸酯（NCP，不是硝基供体）在抑制STAT3激活方面同样有效，这表明这些化合物作为硫代酸盐靶向亲电试剂。JAK1氧化还原开关可能不是酰基亚硝基化合物的靶标，因为NCA对JAK1的催化活性没有影响，仅轻微影响JAK1诱导的LIF受体磷酸化。然而，用NCA或NCP预处理重组人STAT3减少了游离巯基残基的标记。我们发现，在二胺存在的情况下，NCP增强了成年小鼠心肌细胞中STAT3谷胱甘肽化和二聚化，并在非还原条件下改变了STAT3。最后，我们发现在心力衰竭的Gαq模型中，单体STAT3水平以氧化还原敏感的方式降低。总之，我们的证据表明STAT3具有氧化还原敏感的半胱氨酸，可以调节其激活，并被HNO供体和酰基亚硝基化合物靶向。这些发现提出了通过氧化还原依赖的方式靶向STAT3信号的新治疗策略的可能性，特别是在具有显著促炎信号的心脏和非心脏疾病的背景下。
We previously showed that oxidative stress inhibits leukemia inhibitory factor (LIF) signaling by targeting JAK1, and the catalytic domains of JAK 1 and 2 have a cysteine-based redox switch. Thus, we postulated that the NO sibling and thiophylic compound, nitroxyl (HNO), would inhibit LIF-induced JAK-STAT3 activation. Pretreatment of human microvascular endothelial cells (HMEC-1) or neonatal rat cardiomyocytes with the HNO donors Angeli’s salt or nitrosocyclohexyl acetate (NCA) inhibited LIF-induced STAT3 activation. NCA pretreatment also blocked the induction of downstream inflammatory genes (e.g. intercellular adhesion molecule 1, CCAAT/enhancer binding protein delta). The related 1-nitrosocyclohexyl pivalate (NCP; not a nitroxyl donor) was equally effective in inhibiting STAT3 activation, suggesting that these compounds act as thiolate targeting electrophiles. The JAK1 redox switch is likely not a target of acyloxy nitroso compounds, as NCA had no effect on JAK1 catalytic activity and only modestly affected JAK1-induced phosphorylation of the LIF receptor. However, pretreatment of recombinant human STAT3 with NCA or NCP reduced labeling of free sulfhydryl residues. We show that NCP in the presence of diamide enhanced STAT3 glutathionylation and dimerization in adult mouse cardiac myocytes and altered STAT3 under non-reducing conditions. Finally, we show that monomeric STAT3 levels are decreased in the Gαq model of heart failure in a redox-sensitive manner. Altogether, our evidence indicates that STAT3 has redox-sensitive cysteines that regulate its activation and are targeted by HNO donors and acyloxy nitroso compounds. These findings raise the possibility of new therapeutic strategies to target STAT3 signaling via a redox-dependent manner, particularly in the context of cardiac and non-cardiac diseases with prominent pro-inflammatory signaling.
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谷胱甘肽氧化诱导的心律不齐可以通过预防线粒体去极化来抑制。
影响因子：
5
作者：
Brown, David A.;Aon, Miguel A.;Frasier, Chad R.;Sloan, Ruben C.;Maloney, Andrew H.;Anderson, Ethan J.;O'Rourke, Brian
通讯作者：
O'Rourke, Brian
DOI：
10.1073/pnas.0937302100
发表时间：
2003-04-29
影响因子：
11.1
作者：
Paolocci, N;Katori, T;Kass, DA
通讯作者：
Kass, DA
DOI：
10.1073/pnas.94.15.8121
发表时间：
1997-07-22
影响因子：
11.1
作者：
DAngelo, DD;Sakata, Y;Dorn, GW
通讯作者：
Dorn, GW
DOI：
10.1073/pnas.181191198
发表时间：
2001-08-28
影响因子：
11.1
作者：
Paolocci, N;Saavedra, WF;Kass, DA
通讯作者：
Kass, DA
影响因子：
3
作者：
Kim, Yong Sook;Ahn, Youngkeun;Kang, Jung Chaee
通讯作者：
Kang, Jung Chaee