Foxo蛋白在大鼠蛛网膜下腔出血不同脑区中表达及意义
摘要
蛛网膜下腔出血所致的脑血管痉挛往往造成迟发性局部缺血性神经损害,是患者死亡和致残率增加的重要原因。研究表明神经元发生凋亡是缺血缺氧导致神经元迟发性损害的主要机制。在细胞凋亡中作为转录因子的叉头框(forkhead box,Fox)蛋白主要起促进作用。因此,本研究通过枕大池二次注血法制备大鼠SAH模型,观察不同脑区中AKT、FKHR及凋亡相关蛋白的表达,探讨蛛网膜下腔出血的发病机制,为临床治疗脑血管疾病等提供理论基础及治疗靶点。
结果表明:SAH组的神经行为评分明显降低,大脑基底动脉血流速度加快,神经元数目减少,脑水含量明显增加,说明SAH可以造成严重的脑损伤。通过上调脑皮质及脑干Bax/Bcl-2比值,促进神经元凋亡,加重脑损伤。其机制与P-AKT与AKT的比值下降,AKT处于无活性状态,使P-FKHR减少,未磷酸化的FKHR增加,进入胞核激活相关的死亡基因,促进细胞的凋亡有关。FKHR进出细胞核可能还需要14-3-3蛋白的参与。尼莫地平通过上调P-AKT与AKT的比值,激活AKT,增加FKHR的磷酸化,减少其入核,使其不能激活下游的Bax等死亡基因,减轻大脑皮质和脑干的损伤。
结论:P-AKT及14-3-3蛋白通过调控FKHR的入核,进而调控下游的凋亡相关基因参与了大鼠蛛网膜下腔出血所致的损伤过程,而尼莫地平通过上调P-AKT及P-FKHR的表达,减少FKHR,从而减轻SAH所致脑损伤。
Subarachnoid haemorrhage is one of the common emergencies in neurology department. The cerebral vasospasm(CVS)induced by subarachnoid hemorrhage(SAH) was the main cause of delayed ischemic neurological deficit(DIND). CVS was also the main cause of disability and death induced by SAH. We have some knowledege about the mechanism of the CVS. The change of environmental around the vessel, hemoglobin and its metablotes will increase the release of vasocontrictive substances and decrease the release of vasodilator which result in CVS. In addition, the mechanism is related to mechanical strech of intracerebral hematoma. It was found that apoptosis was the main mechanism which resulted in DIND and Fox protein promote apoptosis. AKT and 14-3-3 was involved in regulation of FKHR.
Aim: The SAH model was establish by double injections of blood into cistern magna in Wistar rats. The regulation mechanismof AKT and 14-3-3 for FOXO in and out of the nucleus was explored.
Methods: The rats were randomly divided into three groups:sham group、subarachnoid hemorrhage group(SAH)、subarachnoid hemorrhage+Nimodipine group. A reliable models of subarachnoid hemorrhage (SAH) was establish by double injections of blood into cistern magna in Wistar rats. The neurological score were performed at 24 hours in all group according to Loeffler, respectively. The basilar artery blood flow velocity was measured by transcranial doppler sonography (TCD) and the brain morphological change was measured by HE staining. The cerebral water content was measured by using dry-wet weight method. The expression of FKHR,P-FKHR,AKT, P-FKHR,14-3-3, Bax and Bcl-2 was detected by Westernblotting.
Results and discussion:
The neurological score were performed at 24 hours in all group according to Loeffler, respectively. The results showed that compared with sham group, the neuroethological score of SAH group was obviously decreased. It suggested that SAH can result in brain damage. Compared with SAH group, the neuroethological score of SAH + Nimodipine group was obviously increased. It suggested that Nimodipine can lessen brain damage.
The basilar artery blood flow velocity was measured by TCD. The results showed that compared with sham group, the basilar artery blood flow velocity of SAH group obviously increased. It suggested that the cerebral vasospasm(CVS) can be induced by subarachnoid hemorrhage(SAH). This is the foundamental for the further research. Compared with SAH group, the basilar artery blood flow velocity of SAH + Nimodipine group was obviously decreased. It suggested that Nimodipine can relieve the CVS.
HE staining showed that the number of neuron in SAH group is decreasing. The neuron and glia in SAH group was swelling. Bleeding lesions can also be seen in SAH group. It suggested tha t the cerebral injury was induced by SAH. The number of necrosis neuron in SAH + Nimodipine group is decreasing. It was implied that Nimodipine has protective effect on brain damage induced by SAH.
The cerebral water content was measured by using dry-wet weight method.The results showed that compared with sham group, cerebral water content in SAH was increasing. It suggested that brain edema was induced by SAH. Nimodipine is a kind of selective calcium blocker. It can lessen the brain edema by improving BBB permeability,decreasing [Ca2+]I in neuron and increasing the activity of Ca2+-ATPase.
The brain damage area and cerebral water content in SAH was higher than that of sham group. It suggested that the SAH model is successfully established. It suggested tha t the brain damage was induced by SAH.
The Western blotting results showed that the expression of FKHR in cortex and brain stem in SAH group was obviously increasing, but the expression of P-FKHR and the ratio of P-AKT/AKT in cortex and brain stem in SAH group was obviously decreasing. The expression of FKHR in cortex and brain stem in SAH + Nimodipine group was obviously decreasing, but the expression of P-FKHR and the ratio of P-AKT/AKT in cortex and brain stem in SAH+Nimodipine group was obviously increasing. It suggested that AKT cannot be activated when the ratio of P-AKT/AKT was decreasing in SAH group. So the FKHR cannot be phosphorylation, and it would enter into neucleus, then activated the death gene,such as Bax. The ratio of Bax/Bcl-2 then increased, and apoptosis will occur. After administration of Nimodipine, the ratio of P-AKT/AKT was increasing, AKT can be activated. So the FKHR can be phosphorylation, and it wouldnot enter into neucleus, then the death gene cannot be activated,such as Bax. The ratio of Bax/Bcl-2 then decreased, and survival will occur.
On the other hand, the expression of 14-3-3 in SAH group was decreasing. It suggested that 14-3-3 cannot combine with FKHR, then FKHR enter into neucleus, activated the process of apoptosis.
Conclusion:
1.The neurological score and the number of neuron in SAH group was lower than that of sham group. The basilar artery blood flow velocity and cerebral water content in SAH group was higher than that of sham group. The It suggested that the SAH model is successfully established.
2. The upregulation of Bax and inhibition of Bcl-2 induced by SAH was involved in brain damage.
3. FKHR located into neucleus was the main cause for apoptosis. The mechanism was involved the ratio of P-AKT/AKT decreasing and AKT inactivaed then the FKHR cannot be phosphorylation.
4. 14-3-3 was also involved in the brain damage induced by SAH. When lost of 14-3-3 induced by SAH, it cannot combine with FKHR.
5.Nimodipine can lessen brain damage induced by SAH through upregulation of the ratio of P-AKT/ AKT, activation of AKT, phosphorylation of FKHR and upregulation of 14-3-3.
结果表明:SAH组的神经行为评分明显降低,大脑基底动脉血流速度加快,神经元数目减少,脑水含量明显增加,说明SAH可以造成严重的脑损伤。通过上调脑皮质及脑干Bax/Bcl-2比值,促进神经元凋亡,加重脑损伤。其机制与P-AKT与AKT的比值下降,AKT处于无活性状态,使P-FKHR减少,未磷酸化的FKHR增加,进入胞核激活相关的死亡基因,促进细胞的凋亡有关。FKHR进出细胞核可能还需要14-3-3蛋白的参与。尼莫地平通过上调P-AKT与AKT的比值,激活AKT,增加FKHR的磷酸化,减少其入核,使其不能激活下游的Bax等死亡基因,减轻大脑皮质和脑干的损伤。
结论:P-AKT及14-3-3蛋白通过调控FKHR的入核,进而调控下游的凋亡相关基因参与了大鼠蛛网膜下腔出血所致的损伤过程,而尼莫地平通过上调P-AKT及P-FKHR的表达,减少FKHR,从而减轻SAH所致脑损伤。
Subarachnoid haemorrhage is one of the common emergencies in neurology department. The cerebral vasospasm(CVS)induced by subarachnoid hemorrhage(SAH) was the main cause of delayed ischemic neurological deficit(DIND). CVS was also the main cause of disability and death induced by SAH. We have some knowledege about the mechanism of the CVS. The change of environmental around the vessel, hemoglobin and its metablotes will increase the release of vasocontrictive substances and decrease the release of vasodilator which result in CVS. In addition, the mechanism is related to mechanical strech of intracerebral hematoma. It was found that apoptosis was the main mechanism which resulted in DIND and Fox protein promote apoptosis. AKT and 14-3-3 was involved in regulation of FKHR.
Aim: The SAH model was establish by double injections of blood into cistern magna in Wistar rats. The regulation mechanismof AKT and 14-3-3 for FOXO in and out of the nucleus was explored.
Methods: The rats were randomly divided into three groups:sham group、subarachnoid hemorrhage group(SAH)、subarachnoid hemorrhage+Nimodipine group. A reliable models of subarachnoid hemorrhage (SAH) was establish by double injections of blood into cistern magna in Wistar rats. The neurological score were performed at 24 hours in all group according to Loeffler, respectively. The basilar artery blood flow velocity was measured by transcranial doppler sonography (TCD) and the brain morphological change was measured by HE staining. The cerebral water content was measured by using dry-wet weight method. The expression of FKHR,P-FKHR,AKT, P-FKHR,14-3-3, Bax and Bcl-2 was detected by Westernblotting.
Results and discussion:
The neurological score were performed at 24 hours in all group according to Loeffler, respectively. The results showed that compared with sham group, the neuroethological score of SAH group was obviously decreased. It suggested that SAH can result in brain damage. Compared with SAH group, the neuroethological score of SAH + Nimodipine group was obviously increased. It suggested that Nimodipine can lessen brain damage.
The basilar artery blood flow velocity was measured by TCD. The results showed that compared with sham group, the basilar artery blood flow velocity of SAH group obviously increased. It suggested that the cerebral vasospasm(CVS) can be induced by subarachnoid hemorrhage(SAH). This is the foundamental for the further research. Compared with SAH group, the basilar artery blood flow velocity of SAH + Nimodipine group was obviously decreased. It suggested that Nimodipine can relieve the CVS.
HE staining showed that the number of neuron in SAH group is decreasing. The neuron and glia in SAH group was swelling. Bleeding lesions can also be seen in SAH group. It suggested tha t the cerebral injury was induced by SAH. The number of necrosis neuron in SAH + Nimodipine group is decreasing. It was implied that Nimodipine has protective effect on brain damage induced by SAH.
The cerebral water content was measured by using dry-wet weight method.The results showed that compared with sham group, cerebral water content in SAH was increasing. It suggested that brain edema was induced by SAH. Nimodipine is a kind of selective calcium blocker. It can lessen the brain edema by improving BBB permeability,decreasing [Ca2+]I in neuron and increasing the activity of Ca2+-ATPase.
The brain damage area and cerebral water content in SAH was higher than that of sham group. It suggested that the SAH model is successfully established. It suggested tha t the brain damage was induced by SAH.
The Western blotting results showed that the expression of FKHR in cortex and brain stem in SAH group was obviously increasing, but the expression of P-FKHR and the ratio of P-AKT/AKT in cortex and brain stem in SAH group was obviously decreasing. The expression of FKHR in cortex and brain stem in SAH + Nimodipine group was obviously decreasing, but the expression of P-FKHR and the ratio of P-AKT/AKT in cortex and brain stem in SAH+Nimodipine group was obviously increasing. It suggested that AKT cannot be activated when the ratio of P-AKT/AKT was decreasing in SAH group. So the FKHR cannot be phosphorylation, and it would enter into neucleus, then activated the death gene,such as Bax. The ratio of Bax/Bcl-2 then increased, and apoptosis will occur. After administration of Nimodipine, the ratio of P-AKT/AKT was increasing, AKT can be activated. So the FKHR can be phosphorylation, and it wouldnot enter into neucleus, then the death gene cannot be activated,such as Bax. The ratio of Bax/Bcl-2 then decreased, and survival will occur.
On the other hand, the expression of 14-3-3 in SAH group was decreasing. It suggested that 14-3-3 cannot combine with FKHR, then FKHR enter into neucleus, activated the process of apoptosis.
Conclusion:
1.The neurological score and the number of neuron in SAH group was lower than that of sham group. The basilar artery blood flow velocity and cerebral water content in SAH group was higher than that of sham group. The It suggested that the SAH model is successfully established.
2. The upregulation of Bax and inhibition of Bcl-2 induced by SAH was involved in brain damage.
3. FKHR located into neucleus was the main cause for apoptosis. The mechanism was involved the ratio of P-AKT/AKT decreasing and AKT inactivaed then the FKHR cannot be phosphorylation.
4. 14-3-3 was also involved in the brain damage induced by SAH. When lost of 14-3-3 induced by SAH, it cannot combine with FKHR.
5.Nimodipine can lessen brain damage induced by SAH through upregulation of the ratio of P-AKT/ AKT, activation of AKT, phosphorylation of FKHR and upregulation of 14-3-3.
引文
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