Inhibition of Prolyl Hydroxylase Protects against 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Neurotoxicity MODEL FOR THE POTENTIAL INVOLVEMENT OF THE HYPOXIA-INDUCIBLE FACTOR PATHWAY IN PARKINSON DISEASE
Inhibition of Prolyl Hydroxylase Protects against 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Neurotoxicity MODEL FOR THE POTENTIAL INVOLVEMENT OF THE HYPOXIA-INDUCIBLE FACTOR PATHWAY IN PARKINSON DISEASE
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DOI：
10.1074/jbc.m109.000638
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发表时间：
2009-10-16
影响因子：
4.8
通讯作者：
Andersen, Julie K.
中科院分区：
文献类型：
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作者：
Lee, Donna W.;Rajagopalan, Subramanian;Andersen, Julie K.
缺氧诱导因子 (HIF) 通过调节铁、抗氧化防御和线粒体功能在细胞存活中发挥重要作用。铁依赖性酶类脯氨酰羟化酶 (PHD) 的药理学抑制剂以 HIF 蛋白的 α 亚基为目标进行降解，最近已被证明可以减轻与中风和缺氧缺血性损伤相关的神经变性。在此，我们报道，3,4-二羟基苯甲酸酯（DHB）抑制 PHD 可防止 1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）诱导的黑质多巴胺能细胞丢失，并上调这些神经元内的 HIF-1 α。在 MPTP 存在的情况下，单独 DHB 预处理后，HIF 依赖性基因血红素加氧酶-1 (Ho-1) 和锰超氧化物歧化酶 (Mnsod) 的 mRNA 和蛋白质水平也保持升高。 MPTP 诱导的铁转运蛋白减少以及黑质和纹状体铁水平升高恢复到与未经 DHB 预处理的对照组相当的水平。还发现 DHB 可以减弱 MPTP 导致的丙酮酸脱氢酶 mRNA 和活性的降低。在体外，在用 PHD 抑制剂或铁螯合剂处理、在 3% 氧气中生长的 N27 细胞中，HIF 通路被激活。与我们的体内数据一致，MPP+引起的总铁增加以及细胞活力降低在 DHB 存在下减弱。总而言之，这些数据表明，针对 MPTP 神经毒性的保护可能是通过铁稳态的改变以及对细胞 HIF-1 α 诱导引起的氧化应激和线粒体功能障碍的防御来介导的。这项研究提供了新的数据，将 HIF 诱导的可能治疗效用扩展到帕金森病神经变性模型，这可能不仅对这种疾病本身有益，而且对与金属诱导的氧化应激相关的其他疾病也有益。
Hypoxia-inducible factor (HIF) plays an important role in cell survival by regulating iron, antioxidant defense, and mitochondrial function. Pharmacological inhibitors of the iron-dependent enzyme class prolyl hydroxylases (PHD), which target alpha subunits of HIF proteins for degradation, have recently been demonstrated to alleviate neurodegeneration associated with stroke and hypoxic-ischemic injuries. Here we report that inhibition of PHD by 3,4-dihydroxybenzoate (DHB) protects against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced nigral dopaminergic cell loss and up-regulates HIF-1 alpha within these neurons. Elevations in mRNA and protein levels of HIF-dependent genes heme oxygenase-1 (Ho-1) and manganese superoxide dismutase (Mnsod) following DHB pretreatment alone are also maintained in the presence of MPTP. MPTP-induced reductions in ferroportin and elevations in nigral and striatal iron levels were reverted to levels comparable with that of untreated controls with DHB pretreatment. Reductions in pyruvate dehydrogenase mRNA and activity resulting from MPTP were also found to be attenuated by DHB. In vitro, the HIF pathway was activated in N27 cells grown at 3% oxygen treated with either PHD inhibitors or an iron chelator. Concordant with our in vivo data, the MPP+-elicited increase in total iron as well as decreases in cell viability were attenuated in the presence of DHB. Taken together, these data suggest that protection against MPTP neurotoxicity may be mediated by alterations in iron homeostasis and defense against oxidative stress and mitochondrial dysfunction brought about by cellular HIF-1 alpha induction. This study provides novel data extending the possible therapeutic utility of HIF induction to a Parkinson disease model of neurodegeneration, which may prove beneficial not only in this disorder itself but also in other diseases associated with metal-induced oxidative stress.