Histamine H3 receptors aggravate cerebral ischaemic injury by histamine-independent mechanisms.
Histamine H3 receptors aggravate cerebral ischaemic injury by histamine-independent mechanisms.
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组胺H3受体通过组胺非依赖性机制加重脑缺血损伤
DOI：
10.1038/ncomms4334
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发表时间：
2014-02-25
影响因子：
16.6
通讯作者：
Chen, Zhong
中科院分区：
文献类型：
--
作者：
Yan, Haijing;Zhang, Xiangnan;Hu, Weiwei;Ma, Jing;Hou, Weiwei;Zhang, Xingzhou;Wang, Xiaofen;Gao, Jieqiong;Shen, Yao;Lv, Jianxin;Ohtsu, Hiroshi;Han, Feng;Wang, Guanghui;Chen, Zhong
组胺H3受体（H3R）在脑缺血/再灌注（I/R）损伤中的作用尚不清楚。在这里，我们表明，H3R的表达上调后，I/R在两个小鼠模型。H3R拮抗剂和H3R敲除可减弱I/R损伤，这可被H3R选择性激动剂逆转。有趣的是，H1R和H2R拮抗剂、组氨酸脱羧酶（HDC）抑制剂和HDC敲除均未能损害H3R阻断的保护。H3R阻断抑制mTOR磷酸化并加强自噬。H3R拮抗作用的神经保护作用可被3-甲基腺嘌呤和针对Atg7的siRNA逆转，并且在Atg5 −/−小鼠胚胎成纤维细胞中减弱。此外，阻断CLIC 4与H3Rs结合的肽Tat-H3RCT 414 - 436或针对CLIC 4的siRNA进一步增加I/R诱导的自噬并保护免受I/R损伤。因此，H3R促进I/R损伤，而其拮抗作用通过涉及抑制H3R/CLIC 4结合激活的自噬的组胺非依赖性机制保护免受缺血性损伤，表明H3R抑制是脑缺血的治疗靶点。
The role of the histamine H3 receptor (H3R) in cerebral ischaemia/reperfusion (I/R) injury remains unknown. Here we show that H3R expression is upregulated after I/R in two mouse models. H3R antagonists and H3R knockout attenuate I/R injury, which is reversed by an H3R-selective agonist. Interestingly, H1R and H2R antagonists, a histidine decarboxylase (HDC) inhibitor and HDC knockout all fail to compromise the protection by H3R blockade. H3R blockade inhibits mTOR phosphorylation and reinforces autophagy. The neuroprotection by H3R antagonism is reversed by 3-methyladenine and siRNA forAtg7, and is diminished inAtg5−/−mouse embryonic fibroblasts. Furthermore, the peptide Tat-H3RCT414-436, which blocks CLIC4 binding with H3Rs, or siRNA forCLIC4, further increases I/R-induced autophagy and protects against I/R injury. Therefore, H3R promotes I/R injury while its antagonism protects against ischaemic injury via histamine-independent mechanisms that involve suppressing H3R/CLIC4 binding-activated autophagy, suggesting that H3R inhibition is a therapeutic target for cerebral ischaemia.
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