Redox factor-1 activates endothelial SIRTUIN1 through reduction of conserved cysteine sulfhydryls in its deacetylase domain.
Redox factor-1 activates endothelial SIRTUIN1 through reduction of conserved cysteine sulfhydryls in its deacetylase domain.
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DOI：
10.1371/journal.pone.0065415
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Irani K
中科院分区：
文献类型：
--
作者：
Jung SB;Kim CS;Kim YR;Naqvi A;Yamamori T;Kumar S;Kumar A;Irani K
脱嘌呤/脱嘧啶核酸内切酶1/氧化还原因子-1（APE 1/Ref-1）是一种对血管稳态很重要的还原剂。SIRTUIN 1（SIRT 1）是一种赖氨酸脱乙酰酶，也促进内皮依赖性血管舒张。我们询问APE 1/Ref-1是否控制SIRT 1的氧化还原状态和活性，以及SIRT 1是否介导APE 1/Ref-1对内皮依赖性血管功能的影响。APE 1/Ref-1以还原形式维持SIRT 1中半胱氨酸残基的巯基（硫醇）基团，并促进内皮SIRT 1活性。APE 1/Ref-1通过靶向高度保守的邻位硫醇371和374来刺激SIRT 1活性，所述邻位硫醇371和374在SIRT 1的脱乙酰基酶结构域中形成锌四硫醇基序。APE 1/Ref-1 N端氧化还原结构域中的半胱氨酸残基对于还原SIRT 1和刺激其活性至关重要。APE 1/Ref-1保护内皮SIRT 1免受过氧化氢诱导的巯基氧化和失活。APE 1/Ref-1还促进SIRT 1靶向内皮型一氧化氮合酶（eNOS）的赖氨酸脱乙酰化。SIRT 1在半胱氨酸371和374处突变，这使得它不能被APE 1/Ref-1还原，阻止APE 1/Ref-1对eNOS的赖氨酸脱乙酰化。在APE 1/Ref-1+/−小鼠的所有检查组织（包括血管）中，SIRT 1游离巯基（还原巯基）含量和脱乙酰酶活性均降低。在APE 1/Ref-1+/−小鼠的动脉中过表达SIRT 1可恢复内皮依赖性血管舒张和生物可利用的一氧化氮（NO）至与野生型小鼠相似的水平。因此，APE 1/Ref-1通过维持SIRT 1中功能重要的半胱氨酸巯基处于还原形式，促进内皮SIRT 1活性。APE 1/Ref-1对内皮SIRT 1的这种还原性激活介导了APE 1/Ref-1对eNOS乙酰化的作用，促进内皮源性NO和内皮依赖性血管舒张。
Apurinic/Apyrmidinic Endonuclease 1/Redox Factor-1 (APE1/Ref-1) is a reductant which is important for vascular homeostasis. SIRTUIN1 (SIRT1) is a lysine deacetylase that also promotes endothelium-dependent vasorelaxation. We asked if APE1/Ref-1 governs the redox state and activity of SIRT1, and whether SIRT1 mediates the effect of APE1/Ref-1 on endothelium-dependent vascular function. APE1/Ref-1 maintains sulfhydryl (thiol) groups of cysteine residues in SIRT1 in the reduced form and promotes endothelial SIRT1 activity. APE1/Ref-1 stimulates SIRT1 activity by targeting highly conserved vicinal thiols 371 and 374 which form a zinc tetra-thiolate motif in the deacetylase domain of SIRT1. Cysteine residues in the N-terminal redox domain of APE1/Ref-1 are essential for reducing SIRT1 and stimulating its activity. APE1/Ref-1 protects endothelial SIRT1 from hydrogen peroxide-induced oxidation of sulfhydryls and from inactivation. APE1/Ref-1 also promotes lysine deacetylation of the SIRT1 target endothelial nitric oxide synthase (eNOS). SIRT1 mutated at cysteines 371 and 374, which renders it non-reducible by APE1/Ref-1, prevents lysine deacetylation of eNOS by APE1/Ref-1. SIRT1 free thiol (reduced sulfhydryl) content and deacetylase activity are diminished in all examined tissues of APE1/Ref-1+/− mice, including the vasculature. Overexpression of SIRT1 in aortas of APE1/Ref-1+/− mice restores endothelium-dependent vasorelaxation and bioavailable nitric oxide (NO) to levels similar to those observed in wild-type mice. Thus, APE1/Ref-1, by maintaining functionally important cysteine sulfhydryls in SIRT1 in the reduced form, promotes endothelial SIRT1 activity. This reductive activation of endothelial SIRT1 by APE1/Ref-1 mediates the effect of APE1/Ref-1 on eNOS acetylation, promoting endothelium-derived NO and endothelium-dependent vasorelaxation.
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影响因子：
1.8
作者：
Jiang, Aihua;Gao, Hua;Kelley, Mark R.;Qiao, Xiaoxi
通讯作者：
Qiao, Xiaoxi
DOI：
10.18632/aging.100162
发表时间：
2010-06
期刊：
Aging
影响因子：
--
作者：
Stein S;Schäfer N;Breitenstein A;Besler C;Winnik S;Lohmann C;Heinrich K;Brokopp CE;Handschin C;Landmesser U;Tanner FC;Lüscher TF;Matter CM
通讯作者：
Matter CM
影响因子：
10.8
作者：
Zhang, Qing-jun;Wang, Zhao;Liang, Chih-chuan
通讯作者：
Liang, Chih-chuan
影响因子：
14.9
作者：
Yamamori T;DeRicco J;Naqvi A;Hoffman TA;Mattagajasingh I;Kasuno K;Jung SB;Kim CS;Irani K
通讯作者：
Irani K
DOI：
10.1146/annurev.pathol.4.110807.092250
发表时间：
2010
期刊：
Annual review of pathology
影响因子：
--
作者：
Haigis MC;Sinclair DA
通讯作者：
Sinclair DA