Hemoglobin neurotoxicity is attenuated by inhibitors of the protein kinase CK2 independent of heme oxygenase activity.
Hemoglobin neurotoxicity is attenuated by inhibitors of the protein kinase CK2 independent of heme oxygenase activity.
复制标题
DOI：
10.2174/156720208785425684
复制
发表时间：
2008-08
影响因子：
2.1
通讯作者：
Regan, Raymond F.
中科院分区：
文献类型：
--
作者：
Chen-Roetling, Jing;Li, Zhi;Regan, Raymond F.
血红素加氧酶（HO）酶催化血红素分解的限速步骤，并可能加速暴露于血红素或血红蛋白的神经元的氧化损伤。HO-1和HO-2分别通过磷脂酰肌醇3-激酶(PI3K)/Akt和蛋白激酶C (PKC)/CK2途径在体外激活。本研究验证了CK2、PKC和PI3K抑制剂可以降低小鼠皮质培养物HO活性和神经元对血红蛋白的易感性的假设。用乳酸脱氢酶（LDH）释放和丙二醛（malondidehyde）测定氧化细胞损伤程度。用一氧化碳法测定HO活性。与先前的观察一致，用血红蛋白处理原代皮层培养物16小时导致大约一半的神经元LDH释放和丙二醛增加7倍。CK2抑制剂4,5,6,7-四溴苯并三唑（TBB）和2-二甲基氨基-4,5,6,7-四溴- 1h -苯并咪唑（dat）以及PKC抑制剂GF109203X显著降低了这两个终点；PI3K抑制剂LY294002和wortmannin没有影响。这些抑制剂都没有改变基础HO活性。LY294002和LY303511在很大程度上阻止了血红蛋白处理后1.9倍的活性增加，LY294002的结构类似物LY303511不抑制PI3K的活性。wortmannin、TBB或GF109203X均未降低。这些结果表明，CK2和PKC抑制剂在该模型中的保护作用并不依赖于HO活性的降低。在这个同时表达HO-1和HO-2的培养系统中，HO活性似乎并不主要受PKC/CK2或PI3K途径的调节。
The heme oxygenase (HO) enzymes catalyze the rate-limiting step of heme breakdown, and may accelerate oxidative injury to neurons exposed to heme or hemoglobin. HO-1 and HO-2 are activated in vitro by the phosphatidylinositol 3-kinase (PI3K)/Akt and protein kinase C (PKC)/CK2 pathways, respectively. The present study tested the hypotheses that CK2, PKC, and PI3K inhibitors would reduce both HO activity and neuronal vulnerability to hemoglobin in murine cortical cultures. Oxidative cell injury was quantified by LDH release and malondialdehyde assays. HO activity was assessed by carbon monoxide assay. Consistent with prior observations, treating primary cortical cultures with hemoglobin for 16h resulted in release of approximately half of neuronal LDH and a seven-fold increase in malondialdehyde. Both endpoints were significantly reduced by the CK2 inhibitors 4,5,6,7-tetrabromobenzotriazole (TBB) and 2-dimethyl-amino-4,5,6,7-tetrabromo-1H-benzimidazole (DMAT), and by the PKC inhibitor GF109203X; the PI3K inhibitors LY294002 and wortmannin had no effect. None of these inhibitors altered basal HO activity. The 1.9-fold activity increase observed after hemoglobin treatment was largely prevented by LY294002 and LY303511, a structural analog of LY294002 that does not inhibit PI3K activity. It was not reduced by wortmannin, TBB or GF109203X. These results suggest that the protective effect of CK2 and PKC inhibitors in this model is not dependent on reduction in HO activity. In this culture system that expresses both HO-1 and HO-2, HO activity does not appear to be primarily regulated by the PKC/CK2 or PI3K pathways.
登录
查看更多内容
影响因子：
4.4
作者：
Kim, YH;Choi, KH;Kwon, TK
通讯作者：
Kwon, TK
DOI：
10.1152/ajpheart.00464.2005
发表时间：
2005-10-01
影响因子：
4.8
作者：
Leffler, CW;Balabanova, L;Parfenova, H
通讯作者：
Parfenova, H
DOI：
10.1016/s1385-299x(96)00027-x
发表时间：
1997-05-01
期刊：
BRAIN RESEARCH PROTOCOLS
影响因子：
--
作者：
Ewing, JF;Maines, MD
通讯作者：
Maines, MD
DOI：
10.1152/ajpheart.01059.2002
发表时间：
2003-07-01
影响因子：
4.8
作者：
Leffler, CW;Balabanova, L;Parfenova, H
通讯作者：
Parfenova, H
影响因子：
3.8
作者：
Bulleit, RF;Cui, H
通讯作者：
Cui, H