Hydrogen sulfide protects against chemical hypoxia-induced injury by inhibiting ROS-activated ERK1/2 and p38MAPK signaling pathways in PC12 cells.
Hydrogen sulfide protects against chemical hypoxia-induced injury by inhibiting ROS-activated ERK1/2 and p38MAPK signaling pathways in PC12 cells.
复制标题
DOI：
10.1371/journal.pone.0025921
复制
发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Xiao L
中科院分区：
文献类型：
--
作者：
Lan A;Liao X;Mo L;Yang C;Yang Z;Wang X;Hu F;Chen P;Feng J;Zheng D;Xiao L
硫化氢（H2S）是一种新型的神经调节剂和神经保护剂。氯化钴（CoCl2）是一种众所周知的模拟缺氧剂。我们已经证明H2S可以保护PC12细胞免受cocl2诱导的损伤。然而，丝裂原活化蛋白激酶（MAPK）的成员，特别是细胞外信号调节激酶1/2（ERK1/2）和p38MAPK是否参与H2S对PC12细胞化学缺氧损伤的神经保护尚不清楚。我们观察到，CoCl2诱导转录因子缺氧诱导因子-1α (HIF-1α)的表达，降低半胱硫氨酸-β合成酶（CBS， H2S合成酶）的表达，增加活性氧（ROS）的产生，导致细胞损伤，表现为细胞活力下降，线粒体膜电位（MMP）耗散，caspase-3活化和细胞凋亡。用NaHS （H2S供体）或n -乙酰- l半胱氨酸（NAC） （ROS清除剂）预处理后，其毒性减弱。CoCl2快速激活ERK1/2、p38MAPK和C-Jun n -末端激酶（JNK）。用激酶抑制剂（分别为U0126、SB203580或SP600125）抑制ERK1/2或p38MAPK或JNK，或用RNAi （Si-ERK1/2或Si-p38MAPK）基因沉默ERK1/2或p38MAPK，可显著预防cocl2诱导的损伤。NaHS或NAC预处理不仅可以抑制cocl2诱导的ROS产生，还可以抑制ERK1/2和p38MAPK的磷酸化。因此，我们证明了ERK1/2、p38MAPK和JNK的同时激活参与了cocl2诱导的损伤，H2S通过抑制ros激活的ERK1/2和p38MAPK通路来保护PC12细胞免受化学缺氧诱导的损伤。我们的研究结果表明，ERK1/2、p38MAPK和JNK抑制剂或抗氧化剂可能有助于预防和治疗缺氧诱导的神经元损伤。
Hydrogen sulfide (H2S) has been proposed as a novel neuromodulator and neuroprotective agent. Cobalt chloride (CoCl2) is a well-known hypoxia mimetic agent. We have demonstrated that H2S protects against CoCl2-induced injuries in PC12 cells. However, whether the members of mitogen-activated protein kinases (MAPK), in particular, extracellular signal-regulated kinase1/2(ERK1/2) and p38MAPK are involved in the neuroprotection of H2S against chemical hypoxia-induced injuries of PC12 cells is not understood. We observed that CoCl2 induced expression of transcriptional factor hypoxia-inducible factor-1 alpha (HIF-1α), decreased cystathionine-β synthase (CBS, a synthase of H2S) expression, and increased generation of reactive oxygen species (ROS), leading to injuries of the cells, evidenced by decrease in cell viability, dissipation of mitochondrial membrane potential (MMP) , caspase-3 activation and apoptosis, which were attenuated by pretreatment with NaHS (a donor of H2S) or N-acetyl-L cystein (NAC), a ROS scavenger. CoCl2 rapidly activated ERK1/2, p38MAPK and C-Jun N-terminal kinase (JNK). Inhibition of ERK1/2 or p38MAPK or JNK with kinase inhibitors (U0126 or SB203580 or SP600125, respectively) or genetic silencing of ERK1/2 or p38MAPK by RNAi (Si-ERK1/2 or Si-p38MAPK) significantly prevented CoCl2-induced injuries. Pretreatment with NaHS or NAC inhibited not only CoCl2-induced ROS production, but also phosphorylation of ERK1/2 and p38MAPK. Thus, we demonstrated that a concurrent activation of ERK1/2, p38MAPK and JNK participates in CoCl2-induced injuries and that H2S protects PC12 cells against chemical hypoxia-induced injuries by inhibition of ROS-activated ERK1/2 and p38MAPK pathways. Our results suggest that inhibitors of ERK1/2, p38MAPK and JNK or antioxidants may be useful for preventing and treating hypoxia-induced neuronal injury.
登录
查看更多内容
DOI：
10.1073/pnas.96.22.12866
发表时间：
1999-10-26
影响因子：
11.1
作者：
Alessandrini, A;Namura, S;Bonventre, JV
通讯作者：
Bonventre, JV
影响因子：
4.7
作者：
Hu, Li-Fang;Wong, Peter T. -H.;Bian, Jin-Song
通讯作者：
Bian, Jin-Song
影响因子：
3.7
作者：
Lee, YJ;Cho, HN;Lee, YS
通讯作者：
Lee, YS
影响因子：
4.8
作者：
Kimura, Y;Kimura, H
通讯作者：
Kimura, H
影响因子：
56.9
作者：
GOLDBERG, MA;DUNNING, SP;BUNN, HF
通讯作者：
BUNN, HF