Endogenous SO(2)-dependent Smad3 redox modification controls vascular remodeling.
Endogenous SO(2)-dependent Smad3 redox modification controls vascular remodeling.
复制标题
内源性 SO2 依赖性 Smad3 氧化还原修饰控制血管重塑
DOI：
10.1016/j.redox.2021.101898
复制
发表时间：
2021-05
期刊：
影响因子：
11.4
通讯作者：
Jin H
中科院分区：
文献类型：
--
作者：
Huang Y;Li Z;Zhang L;Tang H;Zhang H;Wang C;Chen SY;Bu D;Zhang Z;Zhu Z;Yuan P;Li K;Yu X;Kong W;Tang C;Jung Y;Ferreira RB;Carroll KS;Du J;Yang J;Jin H
二氧化硫（SO2）已成为一种生理相关的信号分子，在调节血管功能中起着重要作用。然而，SO2影响其上游目标的分子机制一直难以捉摸。在这里，我们表明，SO2可以介导过氧化氢（H2 O2）转化为更有效的氧化剂，过氧单亚硫酸盐，提供了一个途径激活H2 O2的巯基蛋白质半胱氨酸残基转化为次磺酸基团，又名半胱氨酸亚磺酰化。通过使用以位点为中心的化学蛋白质组学，我们定量了血管平滑肌细胞对外源性SO2的反应中的>1000个亚磺酰化事件。值得注意的是，约42%的这些亚磺酰化半胱氨酸受SO2的动态调节，其中包括Smad 3（Mothers against decapentaplegic homolog 3）的半胱氨酸-64，Smad 3是转化生长因子β信号传导的关键转录调节因子。Smad 3在半胱氨酸-64处的亚磺酰化抑制其DNA结合活性，而该位点的突变减弱了SO2对血管紧张素II诱导的血管重塑和高血压的保护作用。总之，我们的研究结果强调了SO2通过氧化还原依赖性机制在血管病理生理学中的重要作用。血管平滑肌细胞来源的内源性SO2调节体内血管重塑和高血压SO2可促进H2 O2介导的蛋白半胱氨酸氧化。化学蛋白质组学揭示Smad 3C 64作为SO2依赖性亚磺酰化的靶点。Smad 3C 64是体内SO2依赖性调节血管功能所必需的。
Sulfur dioxide (SO2) has emerged as a physiological relevant signaling molecule that plays a prominent role in regulating vascular functions. However, molecular mechanisms whereby SO2 influences its upper-stream targets have been elusive. Here we show that SO2 may mediate conversion of hydrogen peroxide (H2O2) to a more potent oxidant, peroxymonosulfite, providing a pathway for activation of H2O2 to convert the thiol group of protein cysteine residues to a sulfenic acid group, aka cysteine sulfenylation. By using site-centric chemoproteomics, we quantified >1000 sulfenylation events in vascular smooth muscle cells in response to exogenous SO2. Notably, ~42% of these sulfenylated cysteines are dynamically regulated by SO2, among which is cysteine-64 of Smad3 (Mothers against decapentaplegic homolog 3), a key transcriptional modulator of transforming growth factor β signaling. Sulfenylation of Smad3 at cysteine-64 inhibits its DNA binding activity, while mutation of this site attenuates the protective effects of SO2 on angiotensin II-induced vascular remodeling and hypertension. Taken together, our findings highlight the important role of SO2 in vascular pathophysiology through a redox-dependent mechanism. Vascular smooth muscle cell-derived endogenous SO2 regulates vascular remodeling and hypertension in vivo. SO2 may facilitate H2O2-mediated protein cysteine oxidation. Chemoproteomics reveals Smad3C64 as a target of SO2-dependent sulfenylation. Smad3C64 is required for SO2-dependent regulation of vascular functions in vivo.
登录
查看更多内容
影响因子：
4.8
作者：
Chai, JJ;Wu, JW;Shi, YG
通讯作者：
Shi, YG
影响因子：
5.6
作者：
Bae, JB;Park, JH;Roe, JH
通讯作者：
Roe, JH
DOI：
10.1016/j.mrfmmm.2008.04.008
发表时间：
2008-08-25
影响因子：
2.3
作者：
Georgiadis, M. M.;Luo, M.;Kelley, M. R.
通讯作者：
Kelley, M. R.
影响因子：
4.6
作者：
Bakhmutova-Albert, Ekaterina V.;Yao, Huirong;Richardson, David E.
通讯作者：
Richardson, David E.
影响因子：
5.3
作者：
Hseu, You-Cheng;Yang, Ting-Yu;Yang, Hsin-Ling
通讯作者：
Yang, Hsin-Ling