Reactive Oxygen Species-Dependent c-Fos/Activator Protein 1 Induction Upregulates Heme Oxygenase-1 Expression by Bradykinin in Brain Astrocytes
Reactive Oxygen Species-Dependent c-Fos/Activator Protein 1 Induction Upregulates Heme Oxygenase-1 Expression by Bradykinin in Brain Astrocytes
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DOI：
10.1089/ars.2009.2957
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发表时间：
2010-12-01
影响因子：
6.6
通讯作者：
Yang, Chuen-Mao
中科院分区：
文献类型：
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作者：
Hsieh, Hsi-Lung;Wang, Hui-Hsin;Yang, Chuen-Mao
血红素加氧酶-1 （HO-1）在脑损伤等组织病理改变中起重要作用。我们之前的研究表明，缓激肽（BK）通过丝裂原活化蛋白激酶和核因子κ B （nf - κ B）在大鼠脑星形胶质细胞（RBA-1）中诱导多种炎症蛋白的表达，包括基质金属蛋白酶-9和COX-2。然而，bk在RBA-1细胞中诱导HO-1表达的分子机制仍然不明确。在这里，我们证明了BK通过B-2 BK受体激活的活性氧（ROS）依赖性信号通路诱导HO-1表达和酶活性。NADPH氧化酶（Nox）依赖的ROS生成导致细胞外信号调节激酶1/2 （ERK1/2）和c-Jun- n末端激酶（JNK）的激活，然后分别激活下游分子NF-kappa B和c-Jun。激活蛋白1 （AP-1）亚基c-Fos通过NF-kappa B和c-Jun的激活而上调，c-Fos与HO-1启动子结合，从而开启HO-1基因的转录。含有AP-1顺式结合位点的大鼠HO-1启动子被确定为连接BK作用的关键结构域。综上所述，这些结果表明，在RBA-1细胞中，通过Nox/ ros依赖性事件激活ERK/NF-kappa B和JNK/c-Jun级联反应，增强c-Fos/AP-1活性是BK诱导HO-1上调和激活的必要条件，此外，ros依赖性nf - e2相关因子2的激活也有助于BK在星形胶质细胞中诱导HO-1。Antioxid。氧化还原信号，13,1829-1844。
Heme oxygenase-1 (HO-1) plays a crucial role in tissue pathological changes such as brain injuries. Our previous studies have demonstrated that bradykinin (BK) induces the expression of several inflammatory proteins, including matrix metalloproteinase-9 and COX-2, via mitogen-activated protein kinases and nuclear factor-kappa B (NF-kappa B) in rat brain astrocytes (RBA-1). However, the molecular mechanisms underlying BK-induced HO-1 expression in RBA-1 cells remain poorly defined. Here we demonstrated that BK induced HO-1 expression and enzymatic activity via a B-2 BK receptor-activated reactive oxygen species (ROS)-dependent signaling pathway. NADPH oxidase (Nox)-dependent ROS generation led to activation of extracellular signal-regulated kinase 1/2 (ERK1/2) and c-Jun-N-terminal kinase (JNK) and then activated the downstream molecules NF-kappa B and c-Jun, respectively. The c-Fos, an activator protein 1 (AP-1) subunit, was upregulated by activation of NF-kappa B and c-Jun, which bound to HO-1 promoter and thereby turned on transcription of HO-1 gene. The rat HO-1 promoter containing a putative AP-1 cis-binding site was identified as a crucial domain linking to BK action. Taken together, these results suggested that in RBA-1 cells, activation of ERK/NF-kappa B and JNK/c-Jun cascades by a Nox/ROS-dependent event enhancing c-Fos/AP-1 activity is essential for HO-1 upregulation and activation induced by BK. Moreover, ROS-dependent NF-E2-related factor 2 activation also contributes to HO-1 induction by BK in astrocytes. Antioxid. Redox Signal. 13, 1829-1844.