ADAR1 exacerbates ischemic brain injury via astrocyte-mediated neuron apoptosis.
ADAR1 exacerbates ischemic brain injury via astrocyte-mediated neuron apoptosis.
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DOI：
10.1016/j.redox.2023.102903
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发表时间：
2023-11
期刊：
影响因子：
11.4
通讯作者：
Chen, Shi-You
中科院分区：
文献类型：
--
作者：
Cai, Dunpeng;Fraunfelder, Mikayla;Fujise, Ken;Chen, Shi-You
星形胶质细胞通过获得功能显性表型影响卒中预后。了解脑缺血/再灌注后星形胶质细胞功能状态的分子机制可能揭示新的治疗策略。作用于RNA的腺苷脱氨酶（ADAR1）是一种RNA编辑酶，通常在星形胶质细胞中不表达，但在缺血性卒中病变的星形胶质细胞中被高度诱导。大脑中动脉闭塞（MCAO） 1h后再灌注，ADAR1表达在第1 ~ 7天急剧升高。旋转体和圆柱体试验显示，ADAR1缺乏显著改善了脑梗死的体积和神经功能缺损，这是由于激活的星形胶质细胞和小胶质细胞数量减少所致。令人惊讶的是，ADAR1主要在星形胶质细胞中表达，而在小胶质细胞中仅少量表达。在原代培养的星形胶质细胞中，ADAR1通过磷脂酰肌醇3-激酶(PI3K)/Akt通路促进星形胶质细胞增殖。此外，ADAR1缺乏抑制MCAO小鼠的脑细胞凋亡以及体外激活的星形胶质细胞条件培养基诱导的神经元。ADAR1通过产生活性氧诱导星形胶质细胞分泌IL-1β、IL-6和TNF-α，从而诱导神经元凋亡。这些结果表明，ADAR1是一种促进缺血性卒中后活化星形胶质细胞增殖的新型调节因子，星形胶质细胞产生多种炎症因子，导致神经元凋亡和缺血性卒中预后恶化。ADAR1在缺血性卒中病变的星形胶质细胞中高度诱导。ADAR1促进脑梗死和脑卒中的神经功能缺损。ADAR1激活星形胶质细胞。ADAR1通过PI3K/Akt通路促进星形胶质细胞增殖。星形胶质细胞ADAR1诱导神经元凋亡。
Astrocytes affect stroke outcomes by acquiring functionally dominant phenotypes. Understanding molecular mechanisms dictating astrocyte functional status after brain ischemia/reperfusion may reveal new therapeutic strategies. Adenosine deaminase acting on RNA (ADAR1), an RNA editing enzyme, is not normally expressed in astrocytes, but highly induced in astrocytes in ischemic stroke lesions. The expression of ADAR1 steeply increased from day 1 to day 7 after middle cerebral artery occlusion (MCAO) for 1 h followed by reperfusion. ADAR1 deficiency markedly ameliorated the volume of the cerebral infarction and neurological deficits as shown by the rotarod and cylinder tests, which was due to the reduction of the numbers of activated astrocytes and microglia. Surprisingly, ADAR1 was mainly expressed in astrocytes while only marginally in microglia. In primary cultured astrocytes, ADAR1 promoted astrocyte proliferation via phosphatidylinositol 3-kinase (PI3K)/Akt pathway. Furthermore, ADAR1 deficiency inhibited brain cell apoptosis in mice with MCAO as well as in activated astrocyte-conditioned medium-induced neurons in vitro. It appeared that ADAR1 induces neuron apoptosis by secretion of IL-1β, IL-6 and TNF-α from astrocytes through the production of reactive oxygen species. These results indicated that ADAR1 is a novel regulator promoting the proliferation of the activated astrocytes following ischemic stroke, which produce various inflammatory cytokines, leading to neuron apoptosis and worsened ischemic stroke outcome. ADAR1 is highly induced in astrocytes in the ischemic stroke lesions. ADAR1 promotes cerebral infarction and neurological deficits in stroke. ADAR1 activates astrocytes. ADAR1 promotes astrocyte proliferation via PI3K/Akt pathway. Astrocyte ADAR1 induces neuron apoptosis.
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影响因子：
6.9
作者：
McCann, Sarah K.;Cramond, Fala;Macleod, Malcolm R.;Sena, Emily S.
通讯作者：
Sena, Emily S.
影响因子：
16.8
作者：
Sakurai M;Shiromoto Y;Ota H;Song C;Kossenkov AV;Wickramasinghe J;Showe LC;Skordalakes E;Tang HY;Speicher DW;Nishikura K
通讯作者：
Nishikura K
DOI：
10.3791/562
发表时间：
2007-01-01
期刊：
Journal of visualized experiments : JoVE
影响因子：
--
作者：
Hilgenberg, Lutz G W;Smith, Martin A
通讯作者：
Smith, Martin A
影响因子：
20.1
作者：
Cai D;Sun C;Zhang G;Que X;Fujise K;Weintraub NL;Chen SY
通讯作者：
Chen SY
影响因子：
2.7
作者：
Brait, Vanessa H.;Jackman, Katherine A.;Pang, Terence Y.
通讯作者：
Pang, Terence Y.