Inhibition of Aryl Hydrocarbon Receptor Attenuates Hyperglycemia-Induced Hematoma Expansion in an Intracerebral Hemorrhage Mouse Model.
Inhibition of Aryl Hydrocarbon Receptor Attenuates Hyperglycemia-Induced Hematoma Expansion in an Intracerebral Hemorrhage Mouse Model.
复制标题
抑制芳基烃受体可减轻脑出血小鼠模型中高血糖引起的血肿扩张
DOI：
10.1161/jaha.121.022701
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发表时间：
2021-10-19
影响因子：
5.4
通讯作者：
Tang J
中科院分区：
文献类型：
--
作者：
Ren R;Lu Q;Sherchan P;Fang Y;Lenahan C;Tang L;Huang Y;Liu R;Zhang JH;Zhang J;Tang J
Hyperglycemia is associated with greater hematoma expansion (HE) and worse clinical prognosis after intracerebral hemorrhage (ICH). However, the clinical benefits of intensive glucose normalization remain controversial, and there are no approved therapies for reducing HE. The aryl hydrocarbon receptor (AHR) has been shown to participate in hyperglycemia‐induced blood–brain barrier (BBB) dysfunction and brain injury after stroke. Herein, we investigated the role of AHR in hyperglycemia‐induced HE in a male mouse model of ICH. CD1 mice (n=387) were used in this study. Mice were subjected to ICH by collagenase injection. Fifty percent dextrose was injected intraperitoneally 3 hours after ICH. AHR knockout clustered regularly interspaced short palindromic repeat was administered intracerebroventricularly to evaluate the role of AHR after ICH. A selective AHR inhibitor, 6,2′,4′‐trimethoxyflavone, was administered intraperitoneally 2 hours or 6 hours after ICH for outcome study. To evaluate the effect of AHR on HE, 3‐methylcholanthrene, an AHR agonist, was injected intraperitoneally 2 hours after ICH. The results showed hyperglycemic ICH upregulated AHR accompanied by greater HE. AHR inhibition provided neurological benefits by restricting HE and preserving BBB function after hyperglycemic ICH. In vivo knockdown of AHR further limited HE and enhanced the BBB integrity. Hyperglycemia directly activated AHR as a physiological stimulus in vivo. The thrombospondin‐1/transforming growth factor‐β/vascular endothelial growth factor axis partly participated in AHR signaling after ICH, which inhibited the expressions of BBB‐related proteins, ZO‐1 and Claudin‐5. AHR may serve as a potential therapeutic target to attenuate hyperglycemia‐induced hematoma expansion and to preserve the BBB in patients with ICH.
