title: Mice lacking the β2 adrenergic receptor have a unique genetic profile before and after focal brain ischaemia.
abstract: The role of the β2AR (β2 adrenergic receptor) after stroke is unclear as pharmacological manipulations of the β2AR have produced contradictory results. We previously showed that mice deficient in the β2AR (β2KO) had smaller infarcts compared with WT (wild-type) mice (FVB) after MCAO (middle cerebral artery occlusion), a model of stroke. To elucidate mechanisms of this neuroprotection, we evaluated changes in gene expression using microarrays comparing differences before and after MCAO, and differences between genotypes. Genes associated with inflammation and cell deaths were enriched after MCAO in both genotypes, and we identified several genes not previously shown to increase following ischaemia (Ccl9, Gem and Prg4). In addition to networks that were similar between genotypes, one network with a central core of GPCR (G-protein-coupled receptor) and including biological functions such as carbohydrate metabolism, small molecule biochemistry and inflammation was identified in FVB mice but not in β2KO mice. Analysis of differences between genotypes revealed 11 genes differentially expressed by genotype both before and after ischaemia. We demonstrate greater Glo1 protein levels and lower Pmaip/Noxa mRNA levels in β2KO mice in both sham and MCAO conditions. As both genes are implicated in NF-κB (nuclear factor κB) signalling, we measured p65 activity and TNFα (tumour necrosis factor α) levels 24 h after MCAO. MCAO-induced p65 activation and post-ischaemic TNFα production were both greater in FVB compared with β2KO mice. These results suggest that loss of β2AR signalling results in a neuroprotective phenotype in part due to decreased NF-κB signalling, decreased inflammation and decreased apoptotic signalling in the brain.
authors.affiliation: *Department of Anesthesia, Stanford University, 300 Pasteur Drive, Grant Building S282, Stanford, CA 94305, U.S.A.
authors.forename: Robin E
authors.initials: RE
authors.lastname: White
authors.affiliation: †Genome Technology Center, Stanford University, 855 S. California Avenue, Palo Alto, CA 94305, U.S.A.
authors.forename: Curtis
authors.initials: C
authors.lastname: Palm
authors.affiliation: *Department of Anesthesia, Stanford University, 300 Pasteur Drive, Grant Building S282, Stanford, CA 94305, U.S.A.
authors.forename: Lijun
authors.initials: L
authors.lastname: Xu
authors.affiliation: *Department of Anesthesia, Stanford University, 300 Pasteur Drive, Grant Building S282, Stanford, CA 94305, U.S.A.
authors.forename: Evelyn
authors.initials: E
authors.lastname: Ling
authors.affiliation: *Department of Anesthesia, Stanford University, 300 Pasteur Drive, Grant Building S282, Stanford, CA 94305, U.S.A.
authors.forename: Mitchell
authors.initials: M
authors.lastname: Ginsburg
authors.affiliation: ‡Department of Computer Science, University of California Santa Barbara, Santa Barbara, CA 931065070, U.S.A.
authors.forename: Bernie J
authors.initials: BJ
authors.lastname: Daigle
authors.forename: Ruquan
authors.initials: R
authors.lastname: Han
authors.affiliation: *Department of Anesthesia, Stanford University, 300 Pasteur Drive, Grant Building S282, Stanford, CA 94305, U.S.A.
authors.forename: Andrew
authors.initials: A
authors.lastname: Patterson
authors.affiliation: ¶Department of Bioengineering, Stanford University, 318 Campus Drive S172, Stanford, CA 94305, U.S.A.
authors.forename: Russ B
authors.initials: RB
authors.lastname: Altman
authors.affiliation: *Department of Anesthesia, Stanford University, 300 Pasteur Drive, Grant Building S282, Stanford, CA 94305, U.S.A.
authors.forename: Rona G
authors.initials: RG
authors.lastname: Giffard
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000503:physiopathology*; D016923:Cell Death; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000235:genetics*; D053263:Gene Regulatory Networks; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D046228:Microarray Analysis; D016328:NF-kappa B / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D018343:Receptors, Adrenergic, beta-2 / Q000172:deficiency* / Q000235:genetics; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D020691:rab GTP-Binding Proteins
chemical_list: D016207:Cytokines; D016328:NF-kappa B; D009419:Nerve Tissue Proteins; C408009:Pmaip1 protein, mouse; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D018343:Receptors, Adrenergic, beta-2; D043562:Receptors, G-Protein-Coupled; D014409:Tumor Necrosis Factor-alpha; D020691:rab GTP-Binding Proteins