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Inhibition of Aryl Hydrocarbon Receptor Attenuates Hyperglycemia‐Induced Hematoma Expansion in an Intracerebral Hemorrhage Mouse Model

BACKGROUND: 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 hydroc...

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Autores principales: Ren, Reng, Lu, Qin, Sherchan, Prativa, Fang, Yuanjian, Lenahan, Cameron, Tang, Lihui, Huang, Yi, Liu, Rui, Zhang, John H., Zhang, Jianmin, Tang, Jiping
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8751882/
https://www.ncbi.nlm.nih.gov/pubmed/34622690
http://dx.doi.org/10.1161/JAHA.121.022701
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author Ren, Reng
Lu, Qin
Sherchan, Prativa
Fang, Yuanjian
Lenahan, Cameron
Tang, Lihui
Huang, Yi
Liu, Rui
Zhang, John H.
Zhang, Jianmin
Tang, Jiping
author_facet Ren, Reng
Lu, Qin
Sherchan, Prativa
Fang, Yuanjian
Lenahan, Cameron
Tang, Lihui
Huang, Yi
Liu, Rui
Zhang, John H.
Zhang, Jianmin
Tang, Jiping
author_sort Ren, Reng
collection PubMed
description BACKGROUND: 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. METHODS AND RESULTS: 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. CONCLUSIONS: AHR may serve as a potential therapeutic target to attenuate hyperglycemia‐induced hematoma expansion and to preserve the BBB in patients with ICH.
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spelling pubmed-87518822022-01-14 Inhibition of Aryl Hydrocarbon Receptor Attenuates Hyperglycemia‐Induced Hematoma Expansion in an Intracerebral Hemorrhage Mouse Model Ren, Reng Lu, Qin Sherchan, Prativa Fang, Yuanjian Lenahan, Cameron Tang, Lihui Huang, Yi Liu, Rui Zhang, John H. Zhang, Jianmin Tang, Jiping J Am Heart Assoc Original Research BACKGROUND: 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. METHODS AND RESULTS: 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. CONCLUSIONS: AHR may serve as a potential therapeutic target to attenuate hyperglycemia‐induced hematoma expansion and to preserve the BBB in patients with ICH. John Wiley and Sons Inc. 2021-10-08 /pmc/articles/PMC8751882/ /pubmed/34622690 http://dx.doi.org/10.1161/JAHA.121.022701 Text en © 2021 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
spellingShingle Original Research
Ren, Reng
Lu, Qin
Sherchan, Prativa
Fang, Yuanjian
Lenahan, Cameron
Tang, Lihui
Huang, Yi
Liu, Rui
Zhang, John H.
Zhang, Jianmin
Tang, Jiping
Inhibition of Aryl Hydrocarbon Receptor Attenuates Hyperglycemia‐Induced Hematoma Expansion in an Intracerebral Hemorrhage Mouse Model
title Inhibition of Aryl Hydrocarbon Receptor Attenuates Hyperglycemia‐Induced Hematoma Expansion in an Intracerebral Hemorrhage Mouse Model
title_full Inhibition of Aryl Hydrocarbon Receptor Attenuates Hyperglycemia‐Induced Hematoma Expansion in an Intracerebral Hemorrhage Mouse Model
title_fullStr Inhibition of Aryl Hydrocarbon Receptor Attenuates Hyperglycemia‐Induced Hematoma Expansion in an Intracerebral Hemorrhage Mouse Model
title_full_unstemmed Inhibition of Aryl Hydrocarbon Receptor Attenuates Hyperglycemia‐Induced Hematoma Expansion in an Intracerebral Hemorrhage Mouse Model
title_short Inhibition of Aryl Hydrocarbon Receptor Attenuates Hyperglycemia‐Induced Hematoma Expansion in an Intracerebral Hemorrhage Mouse Model
title_sort inhibition of aryl hydrocarbon receptor attenuates hyperglycemia‐induced hematoma expansion in an intracerebral hemorrhage mouse model
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8751882/
https://www.ncbi.nlm.nih.gov/pubmed/34622690
http://dx.doi.org/10.1161/JAHA.121.022701
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