*Department of Anesthesia, Stanford University, 300 Pasteur Drive, Grant Building S282, Stanford, CA 94305, U.S.A.
†Genome Technology Center, Stanford University, 855 S. California Avenue, Palo Alto, CA 94305, U.S.A.
ASN Neuro. 2012 Sep 7;4(5):e00096. doi: 10.1042/AN20110020.
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.
β2 肾上腺素能受体（β2AR）在中风后的作用尚不清楚，因为β2AR 的药理学操作产生了相互矛盾的结果。我们之前表明，与 WT（野生型）小鼠（FVB）相比，缺乏β2AR（β2KO）的小鼠在 MCAO（大脑中动脉闭塞）后梗死灶更小，MCAO 是中风的模型。为了阐明这种神经保护的机制，我们使用微阵列比较 MCAO 前后以及基因型之间的差异来评估基因表达的变化。在两种基因型中，与炎症和细胞死亡相关的基因在 MCAO 后均富集，并且我们鉴定了几种以前未显示在缺血后增加的基因（Ccl9、Gem 和 Prg4）。除了基因型之间相似的网络之外，还在 FVB 小鼠中但不在 β2KO 小鼠中鉴定到一个具有 GPCR（G 蛋白偶联受体）核心的网络，该网络包括生物功能，如碳水化合物代谢、小分子生物化学和炎症。对基因型之间差异的分析显示，在缺血前后，有 11 个基因在基因型之间存在差异表达。我们在 sham 和 MCAO 条件下均观察到β2KO 小鼠中 Glo1 蛋白水平升高和 Pmaip/Noxa mRNA 水平降低。由于这两个基因都与 NF-κB（核因子κB）信号传导有关，我们在 MCAO 后 24 小时测量了 p65 活性和 TNFα（肿瘤坏死因子α）水平。与β2KO 小鼠相比，MCAO 诱导的 p65 激活和缺血后 TNFα 产生在 FVB 中均更高。这些结果表明，β2AR 信号的丧失导致部分由于 NF-κB 信号的降低、炎症的减少和大脑中凋亡信号的减少而导致神经保护表型。
