促红细胞生成素及其衍生物抗癫痫大鼠心肌细胞凋亡及机制的研究
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摘要
脑心综合征是指因脑部疾病(癫痫、脑出血、脑缺血、蛛网膜下腔出血、急性颅脑损伤、脑肿瘤、颅内炎症等)引发的神经-体液调节功能紊乱所导致的类似心肌缺血、心律失常、心肌梗塞或心力衰竭的一组症状。Janus激酶/信号转导子和转录激活子(JAK/STAT)通路在多种疾病病理过程中发挥重要作用,参与了癫痫、缺血等脑部疾病的病理过程。促红细胞生成素(EPO)是一种多功能性的细胞因子,除了具有造血活性外,还具有广泛的组织保护活性,可通过激活JAK2/STAT5通路抗细胞凋亡。但大剂量或长期使用EPO可能导致红细胞增多症、高血压、血栓形成等不良作用。近年来的研究发现促红细胞生成素衍生物-氨甲酰化促红细胞生成素(CEPO),有与EPO相当的组织保护作用,而不表现促红细胞生成等不良作用。
本研究应用杏仁核内注射海仁藻酸制备大鼠癫痫动物模型,建模前分别给予大鼠EPO、CEPO、AG490(JAK2抑制剂)尾静脉注射干预,观察大鼠癫痫发作后的行为学改变,及不同时间点心肌细胞凋亡、JAK2/STAT5 mRNA和caspase3、bcl-xl蛋白表达情况。研究结果显示,大鼠癫痫发作后可引起血压增高、心率增快,心肌细胞凋亡增多,JAK2、STAT5a、caspase3、bcl-xl表达增强,细胞凋亡率及JAK2 mRNA、STAT5a mRNA、caspase3、bcl-xl蛋白表达随癫痫时程延长而增高。EPO可通过进一步激活JAK2/STAT5信号通路上调bcl-xl、下调caspase3抗心肌细胞凋亡。CEPO也可通过上调bcl-xl、下调caspase3抗心肌细胞凋亡,且保护作用与EPO相当,但不激活JAK2/STAT5信号通路。
探讨EPO、CEPO抗癫痫大鼠心肌细胞凋亡的作用及机制,可以为EPO、CEPO应用于临床提供理论基础。
Carbamylated EPO(CEPO) is a derivative of erythropoietin(EPO) by subjecting it to carbamylation.Unlike EPO,it does not stimulate erythropoiesis,but effectively protects tissue from injury. A number of signaling pathways,such as Jak2/STAT5 signaling,PI3K signaling,protein kinase C and MAPK,have been implicated in EPO-induced cardioprotection. Since CEPO signals only through EPOR-βcR,the mechanism of CEPO-induced cardiorotection may be different from that of EPO. As an important signal transducing pathway,the Janus kinase/signal transducer and activator of transcription(JAK/STAT) pathway is activated by various cytokines and growth factors.The JAK/STAT pathway plays an important role in growth,proliferation,differentiation,inflammation and apoptosis of cells.More and more studies have shown that the JAK/STAT pathway have important role in pathogenesis of cardiac disease.EPO can activate the STAT family members STAT1, STAT3, and STAT5 rapidly. Although STAT1, STAT3,and STAT5 have been implicated in the regulation of apoptosis, only STAT5 so far has been demonstrated in the anti-apoptotic signaling of EPO.
Epilepsy is a common chronic disease in nervous system,which is often accompanied with complications in course.In the complications,arrhythmia and cardiac arrest are the most harmful,many patients’sudden cardiac death has no reason.In this situation,more and more scholars are carrying out the research on brain-heart syndrome. Whether epilepsy can cause definite changes in cardiovascular function is unclear,and which way such changes is mediated in is also unclear.So the effort to identify such mechanism and to give effective intervention to cerebrocardiac syndrome will have significant meaning. The apoptosis of cardiomyocyte was detected with terminal deoxynucleotidyl transferase-mediated dUDP-nick end labeling (TUNEL) method. Immunohistochemistry was used to detect caspase-3 and bcl-xl. The mRNA expression of JAK2 and STAT5 was detected by in situ hybridization.The study applied epilepsy rat model.At time of 0h,2h,6h,12h,24h after epilepsy,rats were put to death and heart tissues were obtained.To esplore the following questions: First, What is the effect of epilepsy on cardiovascular activity?if epilepsy can increase the apoptosis of cardiac myocyte,lead to myocardial injury ?Second, if CEPO and EPO can decrease the apoptosis rate of cardiac myocyte, lessen myocardial injury with epilepsy ?Third, if CEPO and EPO can affect the expression of caspase3 and bcl-xl?Forth,what is the mechanism of cardioprotection ?And if cardioprotection by the activation of JAK2/STAT5 pathway ?
The main results were as followed:
1.The increase of blood pressure and heart rate in epilepsy-group is more significant than control group(P<0.05).
2.Apoptosis of all rats at different time after epilepsy:There were positive cells in epilepsy 0h group by chance.After 2 hours apoptosis cells began increasing,and nucleus of TUNEL positive apoptosis cells were brown.Then they increased gradually,and at 24 hours it reach the peak(P<0.01).The rate of apoptosis reduced gradually in EPO and CEPO group,and the difference is much significant at 24 hours compared with epilepsy group(P<0.01). The rate of apoptosis increased in AG490 group, and the difference is significant at 24 hours compared with ethanol group(P<0.01).
3.Caspase-3 bcl-xl protein expression:There was weakly positive expression of caspase-3 in cardiomyocyte of epilepsy 0h group. After 2 hours the expression began increasing.Then they increased gradually,and at 24 hours it reach the peak(P<0.01).The expression reduced gradually in EPO and CEPO group,and the difference is much significant at 24 hours compared with epilepsy group(P<0.01). The expression of caspase-3 increased in AG490 group, and the difference is significant at 24 hours compared with ethanol group(P<0.01). The expression of bcl-xl increased gradually in EPO and CEPO group,and the difference is much significant at 24 hours compared with epilepsy group(P<0.01). The expression of bcl-xl reduced in AG490 group, and the difference is significant at 24 hours compared with ethanol group(P<0.05).
4.JAK2/STAT5 mRNA expression: There was weakly positive expression of JAK2/STAT5a mRNA in cardiomyocyte of epilepsy 0h group. After 2 hours the expression began increasing.Then they increased gradually,and at 24 hours it reach the peak(P<0.01).The expression increased gradually in EPO group,and the difference is much significant at 24 hours compared with epilepsy group(P<0.01,P<0.05).The expression of JAK2/STAT5a mRNA reduced in AG490 group, and the difference is significant at 24 hours compared with ethanol group(P<0.01,P<0.05). There were no significant difference in the JAK2/STAT5a mRNA expression of CEPO group compared with epilepsy group.
The main conclusions were as followed:
1.Epilepsy can alter cardiovascular activity acutely,lead to the increase of the apoptosis of cardiac myocyte.
2.The apoptotic rate increase with the prolongation of epileptic time.
3.EPO and CEPO can affect the expression of caspase3 and bcl-xl,decrease the apoptotic rate of cardiac myocyte. EPO and CEPO can decrease the apoptosis induced by epilepsy with no significance.
4.EPO can activate the pathway of JAK2/STAT5.The machanism of anti-apoptosis may be related to the pathway, down-regulating of the expression of caspase3, up-regulating of the expression of bcl-xl. CEPO have no effect on the pathway of JAK2/STAT5.The machanism of anti-apoptosis may be related to other pathway, down-regulating of the expression of caspase3, up-regulating of the expression of bcl-xl.
Backing up all our datas,we found that EPO and CEPO can reduce the apoptosis rate of cardiac myocyte.They may be an effective drug in the therapy of epilepsy and other heart disease in the future.
本研究应用杏仁核内注射海仁藻酸制备大鼠癫痫动物模型,建模前分别给予大鼠EPO、CEPO、AG490(JAK2抑制剂)尾静脉注射干预,观察大鼠癫痫发作后的行为学改变,及不同时间点心肌细胞凋亡、JAK2/STAT5 mRNA和caspase3、bcl-xl蛋白表达情况。研究结果显示,大鼠癫痫发作后可引起血压增高、心率增快,心肌细胞凋亡增多,JAK2、STAT5a、caspase3、bcl-xl表达增强,细胞凋亡率及JAK2 mRNA、STAT5a mRNA、caspase3、bcl-xl蛋白表达随癫痫时程延长而增高。EPO可通过进一步激活JAK2/STAT5信号通路上调bcl-xl、下调caspase3抗心肌细胞凋亡。CEPO也可通过上调bcl-xl、下调caspase3抗心肌细胞凋亡,且保护作用与EPO相当,但不激活JAK2/STAT5信号通路。
探讨EPO、CEPO抗癫痫大鼠心肌细胞凋亡的作用及机制,可以为EPO、CEPO应用于临床提供理论基础。
Carbamylated EPO(CEPO) is a derivative of erythropoietin(EPO) by subjecting it to carbamylation.Unlike EPO,it does not stimulate erythropoiesis,but effectively protects tissue from injury. A number of signaling pathways,such as Jak2/STAT5 signaling,PI3K signaling,protein kinase C and MAPK,have been implicated in EPO-induced cardioprotection. Since CEPO signals only through EPOR-βcR,the mechanism of CEPO-induced cardiorotection may be different from that of EPO. As an important signal transducing pathway,the Janus kinase/signal transducer and activator of transcription(JAK/STAT) pathway is activated by various cytokines and growth factors.The JAK/STAT pathway plays an important role in growth,proliferation,differentiation,inflammation and apoptosis of cells.More and more studies have shown that the JAK/STAT pathway have important role in pathogenesis of cardiac disease.EPO can activate the STAT family members STAT1, STAT3, and STAT5 rapidly. Although STAT1, STAT3,and STAT5 have been implicated in the regulation of apoptosis, only STAT5 so far has been demonstrated in the anti-apoptotic signaling of EPO.
Epilepsy is a common chronic disease in nervous system,which is often accompanied with complications in course.In the complications,arrhythmia and cardiac arrest are the most harmful,many patients’sudden cardiac death has no reason.In this situation,more and more scholars are carrying out the research on brain-heart syndrome. Whether epilepsy can cause definite changes in cardiovascular function is unclear,and which way such changes is mediated in is also unclear.So the effort to identify such mechanism and to give effective intervention to cerebrocardiac syndrome will have significant meaning. The apoptosis of cardiomyocyte was detected with terminal deoxynucleotidyl transferase-mediated dUDP-nick end labeling (TUNEL) method. Immunohistochemistry was used to detect caspase-3 and bcl-xl. The mRNA expression of JAK2 and STAT5 was detected by in situ hybridization.The study applied epilepsy rat model.At time of 0h,2h,6h,12h,24h after epilepsy,rats were put to death and heart tissues were obtained.To esplore the following questions: First, What is the effect of epilepsy on cardiovascular activity?if epilepsy can increase the apoptosis of cardiac myocyte,lead to myocardial injury ?Second, if CEPO and EPO can decrease the apoptosis rate of cardiac myocyte, lessen myocardial injury with epilepsy ?Third, if CEPO and EPO can affect the expression of caspase3 and bcl-xl?Forth,what is the mechanism of cardioprotection ?And if cardioprotection by the activation of JAK2/STAT5 pathway ?
The main results were as followed:
1.The increase of blood pressure and heart rate in epilepsy-group is more significant than control group(P<0.05).
2.Apoptosis of all rats at different time after epilepsy:There were positive cells in epilepsy 0h group by chance.After 2 hours apoptosis cells began increasing,and nucleus of TUNEL positive apoptosis cells were brown.Then they increased gradually,and at 24 hours it reach the peak(P<0.01).The rate of apoptosis reduced gradually in EPO and CEPO group,and the difference is much significant at 24 hours compared with epilepsy group(P<0.01). The rate of apoptosis increased in AG490 group, and the difference is significant at 24 hours compared with ethanol group(P<0.01).
3.Caspase-3 bcl-xl protein expression:There was weakly positive expression of caspase-3 in cardiomyocyte of epilepsy 0h group. After 2 hours the expression began increasing.Then they increased gradually,and at 24 hours it reach the peak(P<0.01).The expression reduced gradually in EPO and CEPO group,and the difference is much significant at 24 hours compared with epilepsy group(P<0.01). The expression of caspase-3 increased in AG490 group, and the difference is significant at 24 hours compared with ethanol group(P<0.01). The expression of bcl-xl increased gradually in EPO and CEPO group,and the difference is much significant at 24 hours compared with epilepsy group(P<0.01). The expression of bcl-xl reduced in AG490 group, and the difference is significant at 24 hours compared with ethanol group(P<0.05).
4.JAK2/STAT5 mRNA expression: There was weakly positive expression of JAK2/STAT5a mRNA in cardiomyocyte of epilepsy 0h group. After 2 hours the expression began increasing.Then they increased gradually,and at 24 hours it reach the peak(P<0.01).The expression increased gradually in EPO group,and the difference is much significant at 24 hours compared with epilepsy group(P<0.01,P<0.05).The expression of JAK2/STAT5a mRNA reduced in AG490 group, and the difference is significant at 24 hours compared with ethanol group(P<0.01,P<0.05). There were no significant difference in the JAK2/STAT5a mRNA expression of CEPO group compared with epilepsy group.
The main conclusions were as followed:
1.Epilepsy can alter cardiovascular activity acutely,lead to the increase of the apoptosis of cardiac myocyte.
2.The apoptotic rate increase with the prolongation of epileptic time.
3.EPO and CEPO can affect the expression of caspase3 and bcl-xl,decrease the apoptotic rate of cardiac myocyte. EPO and CEPO can decrease the apoptosis induced by epilepsy with no significance.
4.EPO can activate the pathway of JAK2/STAT5.The machanism of anti-apoptosis may be related to the pathway, down-regulating of the expression of caspase3, up-regulating of the expression of bcl-xl. CEPO have no effect on the pathway of JAK2/STAT5.The machanism of anti-apoptosis may be related to other pathway, down-regulating of the expression of caspase3, up-regulating of the expression of bcl-xl.
Backing up all our datas,we found that EPO and CEPO can reduce the apoptosis rate of cardiac myocyte.They may be an effective drug in the therapy of epilepsy and other heart disease in the future.
引文
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