H2S attenuates injury after ischemic stroke by diminishing the assembly of CaMKII with ASK1-MKK3-p38 signaling module
H2S attenuates injury after ischemic stroke by diminishing the assembly of CaMKII with ASK1-MKK3-p38 signaling module
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H2S 通过减少 CaMKII 与 ASK1-MKK3-p38 信号模块的组装来减轻缺血性中风后的损伤
DOI：
10.1016/j.bbr.2020.112520
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发表时间：
2020-01
影响因子：
2.7
通讯作者：
Zhang Xun-Bao
中科院分区：
文献类型：
--
作者：
Song Yuan-Jian;Shi Yue;Cui Miao-Miao;Li Man;Wen Xiang-Ru;Zhou Xiao-Yan;Lou He-Qing;Wang Yu-Lan;Qi Da-Shi;Tang Man;Zhang Xun-Bao
脑缺血/再灌注（I/R）损伤是导致学习记忆功能障碍的主要原因。硫化氢（H2S）已被证明在各种神经退行性疾病中具有神经保护作用，包括脑I/R诱导的海马CA 1损伤。然而，其潜在机制尚未完全了解。在本研究中，在脑缺血前，仅用SAM/NaHS（SAM，H2S激动剂，和NaHS，H2S供体）或SAM/NaHS与CaM（CaMKII的激活剂）组合预处理大鼠。Morris水迷宫实验表明SAM/NaHS可减轻脑I/R损伤所致的学习记忆障碍。甲酚紫染色显示海马CA 1区锥体神经元存活情况。SAM/NaHS显著增加细胞存活数，而CaM减弱SAM/NaHS的保护作用。免疫组化结果显示，脑I/R后小胶质细胞Iba 1阳性表达明显增加。与I/R组相比，SAM/NaHS组Iba 1阳性小胶质细胞数量明显减少。免疫共沉淀和免疫印迹显示SAM/NaHS抑制了脑I/R后CaMK II与ASK 1-MKK 3-p38信号模块的组装，从而降低了p38的磷酸化。相反，CaM显著抑制SAM/NaHS的作用。以上结果提示，SAM/NaHS可通过减少CaMK Ⅱ与ASK 1-MKK 3-p38信号模块的组装，下调p38磷酸化，从而抑制脑I/R损伤。
Cerebral ischemia/reperfusion (I/R) injury is a leading cause of learning and memory dysfunction. Hydrogen sulfide (H2S) has been shown to confer neuroprotection in various neurodegenerative diseases, including cerebral I/R-induced hippocampal CA1 injury. However, the underlying mechanisms have not been completely understood. In the present study, rats were pretreated with SAM/NaHS (SAM, an H2S agonist, and NaHS, an H2S donor) only or SAM/NaHS combined with CaM (an activator of CaMKII) prior to cerebral ischemia. The Morris water maze test demonstrated that SAM/NaHS could alleviate learning and memory impairment induced by cerebral I/R injury. Cresyl violet staining was used to show the survival of hippocampal CA1 pyramidal neurons. SAM/NaHS significantly increased the number of surviving cells, whereas CaM weakened the protection induced by SAM/NaHS. The immunohistochemistry results indicated that the number of Iba1-positive microglia significantly increased after cerebral I/R. Compared with the I/R group, the number of Iba1-positive microglia in the SAM/NaHS groups significantly decreased. Co-Immunoprecipitation and immunoblotting were conducted to demonstrate that SAM/NaHS suppressed the assembly of CaMKII with the ASK1-MKK3-p38 signal module after cerebral I/R, which decreased the phosphorylation of p38. In contrast, CaM significantly inhibited the effects of SAM/NaHS. Taken together, the results suggested that SAM/NaHS could suppress cerebral I/R injury by downregulating p38 phosphorylation via decreasing the assembly of CaMKII with the ASK1-MKK3-p38 signal module.
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