Cysteine thiol oxidation on SIRT2 regulates inflammation in obese mice with sepsis.
Cysteine thiol oxidation on SIRT2 regulates inflammation in obese mice with sepsis.
复制标题
DOI：
10.1007/s10753-018-0881-9
复制
发表时间：
2019-03
期刊：
影响因子：
5.1
通讯作者：
Vachharajani V
中科院分区：
文献类型：
--
作者：
Wang X;Buechler NL;Long DL;Furdui CM;Yoza BK;McCall CE;Vachharajani V
肥胖增加了急性疾病如败血症和感染性休克的发病率和死亡率。我们先前表明，脓毒症的早期/过度炎症阶段在患有脓毒症的肥胖小鼠中被夸大;沉默调节蛋白2（SIRT 2）调节肥胖症中的脓毒症-炎症。有证据表明，肥胖伴脓毒症与氧化应激增加有关。目前尚不清楚肥胖伴脓毒症的过度炎症是否反过来调节SIRT 2功能。我们最近发现，SIRT 6在脓毒症的过度炎症过程中的氧化调节其糖酵解功能。这项研究测试了这样一个假设，即增加的氧化应激和直接SIRT 2氧化加重了肥胖伴脓毒症的过度炎症。使用来自具有饮食诱导的肥胖（DIO）的小鼠的脾和肝组织，我们研究了在脓毒症的高炎症和低炎症期间氧化SIRT 2表达与总SIRT 2表达。为了阐明SIRT 2氧化（氧化还原敏感性半胱氨酸的特异性修饰）的机制及其对炎症的影响，我们将SIRT 2上的氧化还原敏感性半胱氨酸Cys 221和Cys 224定点突变为丝氨酸（C221 S和C224 S），用突变体或WT SIRT 2转染HEK 293细胞，并研究SIRT 2酶活性和NF-κ Bp 65脱乙酰化。最后，我们使用RAW 264.7巨噬细胞研究了SIRT 2突变对LPS诱导的炎症的影响。在一个相反的关系，总SIRT 2减少，而氧化SIRT 2表达增加，在过度炎症和SIRT 2不能脱乙酰化NF-κ Bp 65与肥胖败血症的氧化应激增加。在机制上，突变体（C221 S和C224 S）均显示相对于WT SIRT 2，1）SIRT 2酶活性降低，2）NF-κ Bp 65的脱乙酰化降低，和3）响应于LPS的抗炎活性降低。直接氧化通过氧化还原敏感性半胱氨酸调节肥胖伴脓毒症的高炎症期SIRT 2功能半胱氨酸巯基在肥胖伴脓毒症的过度炎症过程中调节SIRT 2
Obesity increases morbidity and mortality in acute illnesses such as sepsis and septic shock. We showed previously that the early/hyper-inflammatory phase of sepsis is exaggerated in obese mice with sepsis; sirtuin 2 (SIRT2) modulates sepsis-inflammation in obesity. Evidence suggests that obesity with sepsis is associated with increased oxidative stress. It is unknown whether exaggerated hyper-inflammation of obesity with sepsis modulates the SIRT2 function in return. We showed recently that SIRT6 oxidation during hyper-inflammation of sepsis modulates its glycolytic function. This study tested the hypothesis that increased oxidative stress and direct SIRT2 oxidation exaggerate hyper-inflammation in obesity with sepsis. Using spleen and liver tissue from mice with diet induced obesity (DIO) we studied oxidized vs. total SIRT2 expression during hyper- and hypo-inflammation of sepsis. To elucidate the mechanism of SIRT2-oxidation (specific modifications of redox sensitive cysteines) and its effect on inflammation, we performed site-directed mutations of redox-sensitive cysteines Cys221 and Cys224 on SIRT2 to serine (C221S and C224S), transfected HEK293 cells with mutants or WT SIRT2, and studied SIRT2 enzymatic activity and NFĸBp65 deacetylation. Finally, we studied effect of SIRT2 mutation on LPS-induced inflammation using RAW 264.7 macrophages. In an inverse relationship, total SIRT2 decreased while oxidized SIRT2 expression increased during hyper-inflammation and SIRT2 was unable to deacetylate NFĸBp65 with increased oxidative stress of obesity with sepsis. Mechanistically, both the mutants (C221S and C224S) show decreased 1) SIRT2 enzymatic activity, 2) deacetylation of NFĸBp65, and 3) anti-inflammatory activity in response to LPS vs. WT SIRT2. Direct oxidation modulates SIRT2 function during hyper-inflammatory phase of obesity with sepsis via redox sensitive cysteines. Cysteine thiols regulate SIRT2 during hyper-inflammation of obesity with sepsis
登录
查看更多内容
影响因子：
7.4
作者：
Hu, Shugun;Liu, Hua;Ha, Yonju;Luo, Xuemei;Motamedi, Massoud;Gupta, Mahesh P.;Ma, Jian-Xing;Tilton, Ronald G.;Zhang, Wenbo
通讯作者：
Zhang, Wenbo
影响因子：
4.1
作者：
Buechler N;Wang X;Yoza BK;McCall CE;Vachharajani V
通讯作者：
Vachharajani V
影响因子：
120.7
作者：
Boomer, Jonathan S.;To, Kathleen;Chang, Kathy C.;Takasu, Osamu;Osborne, Dale F.;Walton, Andrew H.;Bricker, Traci L.;Jarman, Stephen D., II;Kreisel, Daniel;Krupnick, Alexander S.;Srivastava, Anil;Swanson, Paul E.;Green, Jonathan M.;Hotchkiss, Richard S.
通讯作者：
Hotchkiss, Richard S.
影响因子：
15.9
作者：
Jung, U;Norman, KE;Ley, K
通讯作者：
Ley, K
影响因子：
4.8
作者：
Kalous, Kelsey S.;Wynia-Smith, Sarah L.;Smith, Brian C.
通讯作者：
Smith, Brian C.