Brg1-mediated Nrf2/HO-1 pathway activation alleviates hepatic ischemia-reperfusion injury.
Brg1-mediated Nrf2/HO-1 pathway activation alleviates hepatic ischemia-reperfusion injury.
复制标题
Brg1介导的Nrf2/HO-1通路激活减轻肝脏缺血再灌注损伤
DOI：
10.1038/cddis.2017.236
复制
发表时间：
2017-06-01
影响因子：
9
通讯作者：
Hei Z
中科院分区：
文献类型：
--
作者：
Ge M;Yao W;Yuan D;Zhou S;Chen X;Zhang Y;Li H;Xia Z;Hei Z
细胞保护基因血红素加氧酶1 （HO-1）可被核因子e2相关因子2 （Nrf2）核易位诱导。本研究的目的是确定brahma相关基因1 （Brg1）在肝缺血-再灌注（HIR）期间Nrf2/HO-1通路激活中的作用，Brg1是SWI2/ snf2样染色质重塑复合物的催化亚基。我们的研究结果表明，在HIR的CMV-Brg1小鼠中，肝脏Brg1在HIR早期被抑制，而Brg1的过表达减少了氧化损伤。此外，启动子驱动的荧光素酶检测显示，腺病毒转染AML12细胞后，Brg1的过表达选择性地增强了缺氧/再氧化（H/R）处理后HO-1基因的表达，但不影响Nrf2的另一个靶基因NQO1。此外，选择性HO-1抑制剂原卟啉锌抑制HO-1可部分逆转Brg1过表达的肝脏保护作用，而HO-1- adv可减轻AML12细胞的H/R损伤。此外，染色质免疫沉淀分析显示，在H/R的AML12肝细胞中，Nrf2将Brg1过表达募集到HO-1调控区域，而Brg1过表达可以显著增加Brg1蛋白对HO-1的募集，而非NQO1启动子的募集。综上所述，我们的研究结果表明，Brg1在再灌注过程中的恢复可以增强nrf2介导的HO-1的诱导表达，从而有效地增强抗氧化能力，对抗肝细胞损伤。
Cytoprotective gene heme oxygenase 1 (HO-1) could be induced by nuclear factor E2-related factor 2 (Nrf2) nuclear translocation. The purpose of this study was to determine the role of Brahma-related gene 1 (Brg1), a catalytic subunit of SWI2/SNF2-like chromatin remodeling complexes, in Nrf2/HO-1 pathway activation during hepatic ischemia–reperfusion (HIR). Our results showed that hepatic Brg1 was inhibited during early HIR while Brg1 overexpression reduced oxidative injury in CMV-Brg1 mice subjected to HIR. Moreover, promoter-driven luciferase assay showed that overexpression of Brg1 by adenovirus transfection in AML12 cells selectively enhanced HO-1 gene expression after hypoxia/reoxygenation (H/R) treatment but did not affect the other Nrf2 target gene NQO1. Furthermore, inhibition of HO-1 by the selective HO-1 inhibitor zinc protoporphyria could partly reverse the hepatic protective effects of Brg1 overexpression while HO-1-Adv attenuated AML12 cells H/R damage. Further, chromatin immunoprecipitation analysis revealed that Brg1 overexpression, which could significantly increase the recruitment of Brg1 protein to HO-1 but not NQO1 promoter, was recruited by Nrf2 to the HO-1 regulatory regions in AML12 hepatocytes subjected to H/R. In conclusion, our results demonstrated that restoration of Brg1 during reperfusion could enhance Nrf2-mediated inducible expression of HO-1 during HIR to effectively increase antioxidant ability to combat against hepatocytes damage.
登录
查看更多内容
影响因子：
11.2
作者：
Banine, F;Bartlett, C;Sherman, LS
通讯作者：
Sherman, LS
右美托咪定通过抑制 NRK-52E 细胞中的间隙连接来防止缺氧/复氧诱导的细胞凋亡。
影响因子：
6.1
作者：
Luo, Chenfang;Yuan, Dongdong;Hei, Ziqing
通讯作者：
Hei, Ziqing
影响因子：
21.3
作者：
Huang, M;Qian, F;Wen, ZL
通讯作者：
Wen, ZL
影响因子：
64.8
作者：
Foster, Simmie L.;Hargreaves, Diana C.;Medzhitov, Ruslan
通讯作者：
Medzhitov, Ruslan
影响因子：
2.2
作者：
Mamiya, Takashi;Katsuoka, Fumiki;Hosoya, Tomonori
通讯作者：
Hosoya, Tomonori