Bilirubin, formed by activation of heme oxygenase-2, protects neurons against oxidative stress injury
Bilirubin, formed by activation of heme oxygenase-2, protects neurons against oxidative stress injury
复制标题
DOI：
10.1073/pnas.96.5.2445
复制
发表时间：
1999-03-02
影响因子：
11.1
通讯作者：
Snyder, SH
中科院分区：
文献类型：
--
作者：
Doré, S;Takahashi, M;Snyder, SH
血红素加氧酶（HO）催化血红素转化为一氧化碳、铁和胆红素，胆红素立即还原为胆红素（BR）。存在两种HO活性同工酶：HO1（一种诱导热休克蛋白）和HO2（一种组成型且高度集中于神经元）。我们证明了由HO2形成的BR具有神经保护作用。过氧化氢在海马和皮质神经元培养中引起的神经毒性可以通过phorbol酯、phorbol 12-肉豆蔻酸13-乙酸酯（PMA）通过刺激蛋白激酶C来预防。我们观察到，在神经元培养中，通过蛋白激酶C途径磷酸化HO2，增强了HO2的催化活性和BR的积累。在HO2基因缺失的小鼠培养物中，PMA的神经保护作用可被HO抑制剂锡原卟啉IX阻止。此外，BR是一种抗氧化剂，在纳摩尔浓度下具有神经保护作用。
Heme oxygenase (HO) catalyzes the conversion of heme to carbon monoxide, iron, and biliverdin, which is immediately reduced to bilirubin (BR), Two HO active isozymes exist: HO1, an inducible heat shock protein, and HO2, which is constitutive and highly concentrated in neurons. We demonstrate a neuroprotective role for BR formed from HO2. Neurotoxicity elicited by hydrogen peroxide in hippocampal and cortical neuronal cultures is prevented by the phorbol ester, phorbol 12-myristate 13-acetate (PMA) via stimulation of protein kinase C. We observe phosphorylation of HO2 through the protein kinase C pathway with enhancement of HO2 catalytic activity and accumulation of BR in neuronal cultures. The neuroprotective effects of PMA are prevented by the HO inhibitor tin protoporphyrin IX and in cultures from mice with deletion of HO2 gene. Moreover, BR, an antioxidant, is neuroprotective at nanomolar concentrations.