Inactivation of endothelial adenosine A2A receptors protects mice from cerebral ischaemia-induced brain injury

Yaqi Zhou, Xianqiu Zeng, Ge Li, Qiuhua Yang, Jiean Xu, Min Zhang, Xiaoxiao Mao, Yapeng Cao, Lina Wang, Yiming Xu, Yong Wang, Yu Zhang, Zhengshuang Xu, Chaodong Wu, Jiang Fan Chen, Md Nasrul Hoda, Zhiping Liu, Mei Hong, Yuqing Huo

Research output: Contribution to journalArticle

Abstract

Background and Purpose: Inactivation of the gene for adenosine A2A receptors (ADORA2A for humans and Adora2a for rodents) protects against brain injury in experimental stroke. However, the cell-specific pathogenic effects of A2A receptors in thromboembolic stroke and the underlying mechanisms remain undefined. Here, we tested the hypothesis that inhibition of endothelial A2A receptors after thromboembolic stroke improves post-stroke outcomes via down-regulation of inflammation. Experimental Approach: Thromboembolic stroke was induced by embolic middle cerebral artery occlusion in mice. Post-stroke outcomes were determined with neurological deficit scoring, infarct volume, inflammatory marker expression, brain leukocyte infiltration, blood–brain barrier (BBB) leakage, and oedema assessment. Anti-inflammatory effects of silencing the gene for A2A receptors or pharmacological antagonism of these receptors were assessed in vitro. Key Results: Thromboembolic stroke induced Adora2a expression in the brain. Mice globally deficient in Adora2a (Adora2a−/−) were resistant to stroke injury. Mice specifically deficient in endothelial Adora2a (Adora2aΔVEC) showed reduced leukocyte infiltration, BBB leakage, and oedema after stroke, along with attenuated downstream proinflammatory markers, both in vivo and in vitro. The A2A receptor antagonist, KW 6002, also reduced brain injury and inflammation after stroke. Inactivation of ADORA2A inhibited endothelial inflammation via suppression of the NLRP3 inflammasome, down-regulating cleaved caspase 1 and IL-1β expression. Conclusions and Implications: Specific inactivation of endothelial A2A receptors mitigated ischaemic brain injury and improved post-stroke outcomes, at least partly, through anti-inflammatory effects via blockade of NLRP3 inflammasome activity. Our findings may open new approaches to vascular protection after ischaemic stroke.

Original languageEnglish (US)
Pages (from-to)2250-2263
Number of pages14
JournalBritish Journal of Pharmacology
Volume176
Issue number13
DOIs
StatePublished - Jul 1 2019

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Adenosine A2A Receptors
Brain Ischemia
Brain Injuries
Stroke
Inflammasomes
Gene Silencing
Edema
Leukocytes
Anti-Inflammatory Agents
Inflammation
Caspase 1
Middle Cerebral Artery Infarction
Brain
Encephalitis
Interleukin-1
Blood Vessels
Rodentia

ASJC Scopus subject areas

  • Pharmacology

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Inactivation of endothelial adenosine A2A receptors protects mice from cerebral ischaemia-induced brain injury. / Zhou, Yaqi; Zeng, Xianqiu; Li, Ge; Yang, Qiuhua; Xu, Jiean; Zhang, Min; Mao, Xiaoxiao; Cao, Yapeng; Wang, Lina; Xu, Yiming; Wang, Yong; Zhang, Yu; Xu, Zhengshuang; Wu, Chaodong; Chen, Jiang Fan; Hoda, Md Nasrul; Liu, Zhiping; Hong, Mei; Huo, Yuqing.

In: British Journal of Pharmacology, Vol. 176, No. 13, 01.07.2019, p. 2250-2263.

Research output: Contribution to journalArticle

Zhou, Y, Zeng, X, Li, G, Yang, Q, Xu, J, Zhang, M, Mao, X, Cao, Y, Wang, L, Xu, Y, Wang, Y, Zhang, Y, Xu, Z, Wu, C, Chen, JF, Hoda, MN, Liu, Z, Hong, M & Huo, Y 2019, 'Inactivation of endothelial adenosine A2A receptors protects mice from cerebral ischaemia-induced brain injury', British Journal of Pharmacology, vol. 176, no. 13, pp. 2250-2263. https://doi.org/10.1111/bph.14673
Zhou, Yaqi ; Zeng, Xianqiu ; Li, Ge ; Yang, Qiuhua ; Xu, Jiean ; Zhang, Min ; Mao, Xiaoxiao ; Cao, Yapeng ; Wang, Lina ; Xu, Yiming ; Wang, Yong ; Zhang, Yu ; Xu, Zhengshuang ; Wu, Chaodong ; Chen, Jiang Fan ; Hoda, Md Nasrul ; Liu, Zhiping ; Hong, Mei ; Huo, Yuqing. / Inactivation of endothelial adenosine A2A receptors protects mice from cerebral ischaemia-induced brain injury. In: British Journal of Pharmacology. 2019 ; Vol. 176, No. 13. pp. 2250-2263.
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abstract = "Background and Purpose: Inactivation of the gene for adenosine A2A receptors (ADORA2A for humans and Adora2a for rodents) protects against brain injury in experimental stroke. However, the cell-specific pathogenic effects of A2A receptors in thromboembolic stroke and the underlying mechanisms remain undefined. Here, we tested the hypothesis that inhibition of endothelial A2A receptors after thromboembolic stroke improves post-stroke outcomes via down-regulation of inflammation. Experimental Approach: Thromboembolic stroke was induced by embolic middle cerebral artery occlusion in mice. Post-stroke outcomes were determined with neurological deficit scoring, infarct volume, inflammatory marker expression, brain leukocyte infiltration, blood–brain barrier (BBB) leakage, and oedema assessment. Anti-inflammatory effects of silencing the gene for A2A receptors or pharmacological antagonism of these receptors were assessed in vitro. Key Results: Thromboembolic stroke induced Adora2a expression in the brain. Mice globally deficient in Adora2a (Adora2a−/−) were resistant to stroke injury. Mice specifically deficient in endothelial Adora2a (Adora2aΔVEC) showed reduced leukocyte infiltration, BBB leakage, and oedema after stroke, along with attenuated downstream proinflammatory markers, both in vivo and in vitro. The A2A receptor antagonist, KW 6002, also reduced brain injury and inflammation after stroke. Inactivation of ADORA2A inhibited endothelial inflammation via suppression of the NLRP3 inflammasome, down-regulating cleaved caspase 1 and IL-1β expression. Conclusions and Implications: Specific inactivation of endothelial A2A receptors mitigated ischaemic brain injury and improved post-stroke outcomes, at least partly, through anti-inflammatory effects via blockade of NLRP3 inflammasome activity. Our findings may open new approaches to vascular protection after ischaemic stroke.",
author = "Yaqi Zhou and Xianqiu Zeng and Ge Li and Qiuhua Yang and Jiean Xu and Min Zhang and Xiaoxiao Mao and Yapeng Cao and Lina Wang and Yiming Xu and Yong Wang and Yu Zhang and Zhengshuang Xu and Chaodong Wu and Chen, {Jiang Fan} and Hoda, {Md Nasrul} and Zhiping Liu and Mei Hong and Yuqing Huo",
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T1 - Inactivation of endothelial adenosine A2A receptors protects mice from cerebral ischaemia-induced brain injury

AU - Zhou, Yaqi

AU - Zeng, Xianqiu

AU - Li, Ge

AU - Yang, Qiuhua

AU - Xu, Jiean

AU - Zhang, Min

AU - Mao, Xiaoxiao

AU - Cao, Yapeng

AU - Wang, Lina

AU - Xu, Yiming

AU - Wang, Yong

AU - Zhang, Yu

AU - Xu, Zhengshuang

AU - Wu, Chaodong

AU - Chen, Jiang Fan

AU - Hoda, Md Nasrul

AU - Liu, Zhiping

AU - Hong, Mei

AU - Huo, Yuqing

PY - 2019/7/1

Y1 - 2019/7/1

N2 - Background and Purpose: Inactivation of the gene for adenosine A2A receptors (ADORA2A for humans and Adora2a for rodents) protects against brain injury in experimental stroke. However, the cell-specific pathogenic effects of A2A receptors in thromboembolic stroke and the underlying mechanisms remain undefined. Here, we tested the hypothesis that inhibition of endothelial A2A receptors after thromboembolic stroke improves post-stroke outcomes via down-regulation of inflammation. Experimental Approach: Thromboembolic stroke was induced by embolic middle cerebral artery occlusion in mice. Post-stroke outcomes were determined with neurological deficit scoring, infarct volume, inflammatory marker expression, brain leukocyte infiltration, blood–brain barrier (BBB) leakage, and oedema assessment. Anti-inflammatory effects of silencing the gene for A2A receptors or pharmacological antagonism of these receptors were assessed in vitro. Key Results: Thromboembolic stroke induced Adora2a expression in the brain. Mice globally deficient in Adora2a (Adora2a−/−) were resistant to stroke injury. Mice specifically deficient in endothelial Adora2a (Adora2aΔVEC) showed reduced leukocyte infiltration, BBB leakage, and oedema after stroke, along with attenuated downstream proinflammatory markers, both in vivo and in vitro. The A2A receptor antagonist, KW 6002, also reduced brain injury and inflammation after stroke. Inactivation of ADORA2A inhibited endothelial inflammation via suppression of the NLRP3 inflammasome, down-regulating cleaved caspase 1 and IL-1β expression. Conclusions and Implications: Specific inactivation of endothelial A2A receptors mitigated ischaemic brain injury and improved post-stroke outcomes, at least partly, through anti-inflammatory effects via blockade of NLRP3 inflammasome activity. Our findings may open new approaches to vascular protection after ischaemic stroke.

AB - Background and Purpose: Inactivation of the gene for adenosine A2A receptors (ADORA2A for humans and Adora2a for rodents) protects against brain injury in experimental stroke. However, the cell-specific pathogenic effects of A2A receptors in thromboembolic stroke and the underlying mechanisms remain undefined. Here, we tested the hypothesis that inhibition of endothelial A2A receptors after thromboembolic stroke improves post-stroke outcomes via down-regulation of inflammation. Experimental Approach: Thromboembolic stroke was induced by embolic middle cerebral artery occlusion in mice. Post-stroke outcomes were determined with neurological deficit scoring, infarct volume, inflammatory marker expression, brain leukocyte infiltration, blood–brain barrier (BBB) leakage, and oedema assessment. Anti-inflammatory effects of silencing the gene for A2A receptors or pharmacological antagonism of these receptors were assessed in vitro. Key Results: Thromboembolic stroke induced Adora2a expression in the brain. Mice globally deficient in Adora2a (Adora2a−/−) were resistant to stroke injury. Mice specifically deficient in endothelial Adora2a (Adora2aΔVEC) showed reduced leukocyte infiltration, BBB leakage, and oedema after stroke, along with attenuated downstream proinflammatory markers, both in vivo and in vitro. The A2A receptor antagonist, KW 6002, also reduced brain injury and inflammation after stroke. Inactivation of ADORA2A inhibited endothelial inflammation via suppression of the NLRP3 inflammasome, down-regulating cleaved caspase 1 and IL-1β expression. Conclusions and Implications: Specific inactivation of endothelial A2A receptors mitigated ischaemic brain injury and improved post-stroke outcomes, at least partly, through anti-inflammatory effects via blockade of NLRP3 inflammasome activity. Our findings may open new approaches to vascular protection after ischaemic stroke.

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