title: Stress-responsive heme oxygenase-1 isoenzyme participates in Toll-like receptor 4-induced inflammation during brain ischemia.
abstract: Toll-like receptors (TLRs) are involved in the progression of ischemic brain injury and hence vascular dementia; however, the underlying mechanisms are largely unknown. Here, we have investigated the interrelationship between stress-responsive heme oxygenase (HO)-1 isoenzyme and TLR4 during chronic brain hypoperfusion. The right unilateral common carotid artery occlusion was performed by ligation of the right common carotid artery in C57BL/6J mice. The brain cortex or hippocampus was removed for western blotting and confocal immunofluorescence analysis. The link between HO-1 and TLR4 was further examined by silencing TLR4 and pharmacological inhibition of HO-1 in primary cultured cortical neurons. Cognitive dysfunction and decrease in cerebral blood flow in mice were observed 4 weeks after the occlusion. Our data further show that common carotid artery occlusion induced an increase in TLR4 and HO-1 protein levels. Although the administration of CoPP (10 mg/kg), HO-1 agonist, improved the cognitive dysfunction in a mice model of occlusion, western blot analysis in primary cultured cortical neurons showed that HO-1 was upregulated after lipopolysaccharide treatment; this was partially abolished by the TLR4 siRNA interference. The flow cytometry analysis showed that pharmacological inhibition of HO-1 by ZnPP (100 μM) further exaggerated lipopolysaccharide-induced neuronal cell death. Hence, stress-responsive HO-1 isoenzyme participates in TLR4-induced inflammation during chronic brain ischemia. The pharmacological manipulation of TLR4 or the HO-1 antioxidant defense pathway may represent a novel treatment strategy for neuronal protection in vascular dementia.
authors.affiliation: aSchool of Medicine, Zhejiang University City College bInstitute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University cDepartment of Pharmacy, First Affiliated Hospital of Zhejiang University, School of Medicine dDepartment of Neurology, Second Affiliated Hospital of Zhejiang University, School of Medicine, Hangzhou, Zhejiang, China eDepartment of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
authors.forename: Rui
authors.initials: R
authors.lastname: Wang
authors.forename: Shu-Ting
authors.initials: ST
authors.lastname: Wang
authors.forename: Yu-Di
authors.initials: YD
authors.lastname: Wang
authors.forename: Gang
authors.initials: G
authors.lastname: Wu
authors.forename: Yan
authors.initials: Y
authors.lastname: Du
authors.forename: Man-Qing
authors.initials: MQ
authors.lastname: Qian
authors.forename: Xing-Guang
authors.initials: XG
authors.lastname: Liang
authors.forename: Mahmoud H
authors.initials: MH
authors.lastname: Elbatreek
authors.forename: Hong-Yu
authors.initials: HY
authors.lastname: Yang
authors.forename: Zhi-Rong
authors.initials: ZR
authors.lastname: Liu
authors.forename: Kohji
authors.initials: K
authors.lastname: Fukunaga
authors.forename: Jian-Xiang
authors.initials: JX
authors.lastname: Liu
authors.forename: Ying-Mei
authors.initials: YM
authors.lastname: Lu
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D017304:Annexin A5 / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002545:Brain Ischemia / Q000150:complications*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D003072:Cognition Disorders / Q000209:etiology; D004622:Embryo, Mammalian; D004660:Encephalitis / Q000209:etiology* / Q000473:pathology; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000502:physiology; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D013315:Stress, Psychological / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
chemical_list: D017304:Annexin A5; D008070:Lipopolysaccharides; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D034741:RNA, Small Interfering; D051197:Toll-Like Receptor 4; D051547:Heme Oxygenase-1