Neuronal NOS-mediated nitration and inactivation of manganese superoxide dismutase in brain after experimental and human brain injury
Neuronal NOS-mediated nitration and inactivation of manganese superoxide dismutase in brain after experimental and human brain injury
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DOI：
10.1111/j.1471-4159.2006.04353.x
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发表时间：
2007-04-01
影响因子：
4.7
通讯作者：
Kochanek, Patrick M.
中科院分区：
文献类型：
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作者：
Bayir, Hulya;Kagan, Valerian E.;Kochanek, Patrick M.
锰超氧化物歧化酶（MnSOD）提供了对抗线粒体中产生的超氧化物的第一道防线。SOD与一氧化氮竞争与超氧化物的反应，并防止过氧亚硝酸盐的产生，过氧亚硝酸盐是一种有效的氧化剂，可以修饰蛋白质形成3-硝基酪氨酸。因此，需要足够量的催化活性MnSOD来防止线粒体损伤。据报道，创伤性脑损伤（TBI）后硝基酪氨酸免疫反应性增加;然而，尚未确定含有修饰的酪氨酸残基的特定蛋白质靶点和这种修饰的功能后果。在这项研究中，我们表明，MnSOD是酪氨酸硝化的目标，这是与TBI后在小鼠的酶活性降低。从TBI病例与死于与CNS创伤无关的原因的对照患者中获得的颞叶皮质样本中获得了类似的发现。在实验性TBI后2 h和24 h与72 h检测到硝基酪氨酸免疫反应性增加，并与神经元标记物NeuN共定位。抑制和/或遗传缺陷的神经元型一氧化氮合酶（nNOS），但不是内皮型一氧化氮合酶（eNOS）衰减MnSOD硝化TBI后。在TBI后24 h，小鼠脑中主要是多形核白细胞积聚，而在损伤后72 h，巨噬细胞是主要的炎性细胞类型。然而，诱导型一氧化氮合酶（iNOS）的选择性抑制剂或遗传缺陷未能影响MnSOD硝化。MnSOD的硝化可能是TBI后神经元细胞内环境中过氧亚硝酸盐的结果。MnSOD的硝化和失活可导致脑内氧化应激的自我放大，使过氧亚硝酸盐的产生和继发性损伤逐步增强。
Manganese superoxide dismutase (MnSOD) provides the first line of defense against superoxide generated in mitochondria. SOD competes with nitric oxide for reaction with superoxide and prevents generation of peroxynitrite, a potent oxidant that can modify proteins to form 3-nitrotyrosine. Thus, sufficient amounts of catalytically competent MnSOD are required to prevent mitochondrial damage. Increased nitrotyrosine immunoreactivity has been reported after traumatic brain injury (TBI); however, the specific protein targets containing modified tyrosine residues and functional consequence of this modification have not been identified. In this study, we show that MnSOD is a target of tyrosine nitration that is associated with a decrease in its enzymatic activity after TBI in mice. Similar findings were obtained in temporal lobe cortical samples obtained from TBI cases versus control patients who died of causes not related to CNS trauma. Increased nitrotyrosine immunoreactivity was detected at 2 h and 24 h versus 72 h after experimental TBI and co-localized with the neuronal marker NeuN. Inhibition and/or genetic deficiency of neuronal nitric oxide synthase (nNOS) but not endothelial nitric oxide synthase (eNOS) attenuated MnSOD nitration after TBI. At 24 h after TBI, there was predominantly polymorphonuclear leukocytes accumulation in mouse brain whereas macrophages were the predominant inflammatory cell type at 72 h after injury. However, a selective inhibitor or genetic deficiency of inducible nitric oxide synthase (iNOS) failed to affect MnSOD nitration. Nitration of MnSOD is a likely consequence of peroxynitrite within the intracellular milieu of neurons after TBI. Nitration and inactivation of MnSOD could lead to self-amplification of oxidative stress in the brain progressively enhancing peroxynitrite production and secondary damage.