BAX contributes to apoptotic-like death following neonatal hypoxia-ischemia: Evidence for distinct apoptosis pathways
BAX contributes to apoptotic-like death following neonatal hypoxia-ischemia: Evidence for distinct apoptosis pathways
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DOI：
10.1007/bf03401871
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发表时间：
2001-09-01
影响因子：
5.7
通讯作者：
Holtzman, DM
中科院分区：
文献类型：
--
作者：
Gibson, ME;Han, BH;Holtzman, DM
背景：新生儿脑缺氧缺血 (H-I) 损伤已被证明会导致具有急性兴奋性毒性/坏死特征的快速细胞死亡，以及具有细胞凋亡特征（例如显着的 caspase-3 激活）的显着延迟细胞死亡。 BAX 是一种促凋亡分子，已被证明是正常发育期间神经元细胞凋亡所必需的，但尚未研究内源性 BAX 在 H-I 损伤发育或成年大脑后的细胞死亡途径中的作用。材料和方法：对出生后第 7 天的 Bax +/+、+/- 和 -/- 小鼠进行单侧颈动脉结扎，然后暴露于 8% 氧气中 45 分钟。在 H-I 后的不同时间点，通过常规组织学、免疫组织化学、免疫荧光、蛋白质印迹和酶测定对脑组织进行研究，以确定细胞损伤的程度和类型以及 caspase 激活的量。 结果：我们发现 bax -/- 小鼠的海马组织损失明显少于表达 bax 的小鼠（38%）。然而，bax -/- 小鼠中剩余的一些细胞死亡仍然具有细胞凋亡的特征，包括核收缩和 caspase-3 激活的证据。尽管与 H-I 后表达 bax 的小鼠相比，bax -/- 小鼠的 caspase-3 活化显着降低，但 bax +/- 和 bax -/- 小鼠海马 CA3 区域中具有活化 caspase-8 的细胞密度在 bax +/- 和 bax -/- 小鼠之间没有差异。 结论：这些发现表明，内源性 BAX 在调节新生儿 H-I 后中枢神经系统 (CNS) 细胞死亡中发挥作用。脑瘫模型。此外，虽然 BAX 似乎可以调节新生儿 H-I 后的 caspase-3 激活，但与死亡受体激活相关的 caspase-8 可能以不依赖于 BAX 的方式导致细胞凋亡样神经元死亡。
Background: Hypoxic-ischemic (H-I) injury to the neonatal brain has been shown to result in rapid cell death with features of acute excitotoxicity/necrosis as well as prominent delayed cell death with features of apoptosis such as marked caspase-3 activation. BAX, a pro-apoptotic molecule, has been shown to be required for apoptotic neuronal cell death during normal development but the contribution of endogenous BAX in cell death pathways following H-I injury to the developing or adult brain has not been studied.Materials and Methods: Bax +/+, +/-, and -/- mice at post-natal day 7 were subjected to unilateral carotid ligation followed by exposure to 45 minutes of 8% oxygen. At different timepoints following H-I, brain tissue was studied by conventional histology, immunohistochemistry, immunofluorescence, Western blotting, and enzymatic assay to determine the extent and type of cell injury as well as the amount of caspase activation.Results: We found that bax -/- mice had significantly less (38%) hippocampal tissue loss than mice expressing bax. Some of the remaining cell death in bax -/- mice, however, still had features of apoptosis including evidence of nuclear shrinkage and caspase-3 activation. Though bax -/- mice had significantly decreased caspase-3 activation as compared to bax expressing mice following H-I, the density of cells with activated caspase-8 in the CA3 region of the hippocampus did not differ between bax +/- and bax -/- mice.Conclusions: These findings demonstrate that endogenous BAX plays a role in regulating cell death in the central nervous system (CNS) following neonatal H-I. a model of cerebral palsy. in addition, while BAX appears to modulate the caspase-3 activation following neonatal H-I, caspase-8 which is linked to death receptor activation, may contribute to apoptotic-like neuronal death in a BAX-independent manner.