Blunting type 1 insulin-like growth factor receptor expression exacerbates neuronal apoptosis following hypoxic/ischemic injury.
Blunting type 1 insulin-like growth factor receptor expression exacerbates neuronal apoptosis following hypoxic/ischemic injury.
复制标题
DOI：
10.1186/1471-2202-12-64
复制
发表时间：
2011-06-30
期刊：
影响因子：
2.4
通讯作者：
Ye P
中科院分区：
文献类型：
--
作者：
Liu W;D'Ercole JA;Ye P
大量的实验数据表明胰岛素样生长因子（IGF）在保护神经元细胞免受损伤（包括缺氧/缺血（H/I）损伤，缺氧/缺血是神经元死亡的主要原因）中具有重要作用。虽然IGFs与神经元或神经胶质1型IGF受体（IGF 1 R）的特异性相互作用已被证明是发育过程中IGF作用所必需的，但在H/I损伤后尚未直接证明。为了直接研究H/I损伤后神经元IGF 1 R的作用，我们利用条件突变nes-igf 1 r-/Wt小鼠，并确定了表达nestin的神经元前体及其后代中IGF 1 R单倍缺陷对H/I诱导的海马神经元损伤和凋亡的影响。H/I在出生后第10天在对照组和nes-igf 1 r-/Wt小鼠中诱导了结扎的右颈总动脉同侧的大脑半球和海马的显著损伤。然而，IGF 1 R表达的减弱明显加剧了H/I诱导的损伤，并增加了死亡率。在同侧半球和海马，nes-igf 1 r-/Wt小鼠的梗死面积是对照组的两倍。nes-igf 1 r-/Wt小鼠同侧半球和海马的大小比对照组大15%至17%，反映了更严重的水肿。与其对梗死面积的影响一致，IGF 1 R单倍缺陷导致nes-igf 1 r-/Wt小鼠同侧海马神经元的减少。神经元的减少主要是由于神经元凋亡的增加。通过核固缩、TUNEL和caspase-3标记判断，nes-igf 1 r-/Wt小鼠损伤后凋亡细胞明显多于对照组。为了确定IGF 1 R作用的可能机制，测定了促存活蛋白IAP-1和XIAP的mRNA表达。与对照组相比，IGF 1 R或IGF-I表达减弱的小鼠脑中cIAP-1和XIAP mRNA的丰度明显降低，而IGF-I过表达的转基因小鼠脑中cIAP-1和XIAP mRNA的丰度则升高。神经元细胞中的IGF 1 R对于H/I损伤后的存活至关重要，并且IGF上调的神经元cIAP-1和XIAP表达可能部分有助于IGF-IGF 1 R保护H/I损伤后的神经元凋亡。
Abundant experimental data have implicated an important role for insulin-like growth factor (IGF) in protecting neuronal cells from injury, including hypoxia/ischemia (H/I) injury, a major cause of neuron death. While the specific interaction of IGFs with neuronal or glial type 1 IGF receptors (IGF1R) has been shown to be essential to IGF actions during development, the same has not been directly demonstrated following H/I injury. To directly examine the role of neuronal IGF1R following H/I injury, we utilized conditional mutant nes-igf1r-/Wt mice and determined the impact of IGF1R haplodeficiency specifically in nestin-expressing neuronal precursors and their progeny on H/I-induced neuronal damage and apoptosis in hippocampus. H/I induced significant damage to the cerebral hemisphere and hippocampus ipsilateral to the ligated right common carotid artery both in control and nes-igf1r-/Wt mice at postnatal day 10. Blunting IGF1R expression, however, markedly exacerbated H/I-induced damage and appeared to increase mortality. In the ipsilateral hemisphere and hippocampus, nes-igf1r-/Wt mice had infarct areas double the size of those in controls. The size of the ipsilateral hemisphere and hippocampus in nes-igf1r-/Wt mice were 15% to 17% larger than those in controls, reflecting more severe edema. Consistent with its effects on infarct area, IGF1R haplodeficiency causes a greater decrease in neurons in the ipsilateral hippocampus of nes-igf1r-/Wt mice. The reduction in neurons was largely due to increases in neuronal apoptosis. Judged by pyknotic nuclei, TUNEL and caspase-3 labeling, nes-igf1r-/Wt mice had significantly more apoptotic cells than that in controls after injury. To determine possible mechanisms of IGF1R actions, the mRNA expression of the pro-survival proteins IAP-1 and XIAP was determined. Compared to controls, the abundance of cIAP-1 and XIAP mRNA was markedly suppressed in mice with blunted IGF1R or IGF-I expression, while was increased in the brain of IGF-I overexpressing transgenic mice. IGF1R in neuronal cells is critically important for their survival following H/I injury, and IGF-upregulated expression of neuronal cIAP-1 and XIAP likely in part contributes to IGF-IGF1R protection against neuronal apoptosis following H/I injury.
登录
查看更多内容
影响因子：
3.6
作者：
MUJSCE, DJ;CHRISTENSEN, MA;VANNUCCI, RC
通讯作者：
VANNUCCI, RC
影响因子：
2.9
作者：
Lin, SY;Fan, LW;Cai, ZW
通讯作者：
Cai, ZW
影响因子：
5.3
作者：
Lin, Shuying;Fan, Lir-Wan;Rhodes, Philip G.;Cai, Zhengwei
通讯作者：
Cai, Zhengwei
影响因子：
64.5
作者：
LIU, JP;BAKER, J;EFSTRATIADIS, A
通讯作者：
EFSTRATIADIS, A
影响因子：
2.9
作者：
CHOMCZYNSKI, P;SACCHI, N
通讯作者：
SACCHI, N