热休克蛋白90介导二氮嗪对抗心脏低温保存损伤的作用和机制研究
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摘要
背景
心脏移植是一种用于治疗严重冠心病等终末期心脏病患者的有效的外科手段,成功的器官保存是心脏移植手术成功的必要前提。然而,目前临床上心脏的低温保存时间局限在4至6h以内,这与其它器官如肝、肾、胰的保存时间相比要短的多。如何有效地延长供心的保存时间是当前迫切需要解决的问题。研究发现在Celsior心脏保存液中添加二氮嗪,能促进长时低温保存后心功能的恢复并减少心肌细胞凋亡。热休克蛋白90(Heat shock protein 90,Hsp90)是一类高度保守的蛋白质家族的成员之一。Hsp90表达增加可诱导细胞保护作用,其机制被认为与其抗凋亡作用相关。然而,Hsp90是否参与了二氮嗪对抗低温保存诱导的心肌细胞凋亡作用尚不明了。
目的
研究Hsp90是否参与了二氮嗪对抗低温保存诱导的心功能下降,同时探究其可能机制。
方法
(1)低温保存模型的建立及心功能测定：离体大鼠心脏于Langendorff恒压灌注装置上平衡后,经主动脉根部灌注40C的Celsior'心麻痹液,灌注时间控制在3min以内,心脏表面同时降温,待心脏停跳后分别置于不同成分的心麻痹液中(4℃)保存,3、6、或9h后心脏被重新置于Langendorff装置上再灌注60min。灌注条件同保存前保持一致。通过MedLab生物信号采集处理系统观察左心室发展压(LVDP)。
(2)细胞凋亡测定：取复灌末期大鼠左心室心尖部分,用TUNEL法观察细胞凋亡情况。计算阳性凋亡细胞占总细胞数的百分比即为细胞凋亡指数(apoptosis index,AI)
(3)Bid表达：取复灌末期大鼠心脏左心室心尖部分,匀浆提蛋白,用Western Blot来检测Bid和tBid蛋白表达情况。
(4)Hsp90表达：取复灌末期大鼠心脏左心室心尖部分,用RT-PCR检测Hsp90mRNA水平,用Western Blot来检测Hsp90蛋白质水平
结果
(1)心脏于单纯Celsior保存液中低温保存3-9 h后,于复灌60 min末测得各组心脏LVDP'恢复率随着保存时间的延长而逐渐降低,心肌细胞凋亡指数随着保存时间的延长而逐渐升高。而与单纯Celsior保存液组相比,心脏在添加了二氮嗪(30μtM)的保存液中保存9h后LVDP'恢复率显著增高,心肌细胞凋亡指数显著下降。
(2)心脏于单纯Celsior保存液中低温保存3h后,Bid蛋白表达量与对照组无明显差异,且无明显裂解。低温保存6h或9h后,Bid裂解后产生的tBid(truncated Bid)片段量显著增加；然而,在心脏保存液中添加二氮嗪后,Bid裂解明显受抑制。
(3)与对照组相比,心脏于Celsior液低温保存3h,Hsp90 mRNA与蛋白表达水平均明显增加。但随着保存时间延长至6-9 h,Hsp90 mRNA与蛋白表达水平却逐渐降低。与9h单纯保存液组相比,二氮嗪组心脏Hsp90 mRNA与蛋白表达水平均显著提高。
(4)17-AAG可部分取消二氮嗪增加低温保存心脏LVDP恢复率的作用。此外,与二氮嗪组相比,保存液中同时添加17-AAG和二氮嗪,Bid裂解产物tBid含量显著增加,心肌细胞凋亡显著增加。
结论二氮嗪可抑制低温保存诱导的心肌细胞Bid蛋白裂解与细胞凋亡,其机制可能与Hsp90表达增加有关。
Background
Heart transplantation is a surgical transplant procedure performed on patients with end-stage heart failure or severe coronary artery disease. Successful organ preservation is the premise for clinical organ transplantation. However, hypothermic preservation of the heart has a limit of about 4-6 h, which is much lower than that for the liver, kidney, and pancreas.Prolonged donor heart preservation becomes more important in cardiovascular surgery. We have reported that diazoxide as a supplementation in Celsior preservation solution, can improve myocardial function and decrease apoptosis during long- term hypothermic preservation. However, the exact anti-apoptotic mechanism of diazoxide is still unknown. The heat shock proteins (Hsps) are highly conserved families of proteins, the cytoprotective function of Hsp90 is largely explained by their anti-apoptotic function, since Hsp90 has been shown to interact with different key apoptotic proteins.
Objectives
To investigate whether heat shock protein 90 (Hsp90) plays an important role in the anti-apoptotic effect of diazoxide in hypothermic preservation rat hearts.
Methods
(1) In vitro hypothermic heart preservation model and cardiac function assay: Male SD rat hearts were quickly removed and washed in cold Krebs-Henseleit (KH) solution. Then hearts were mounted on the Langendorff perfusion apparatus, and perfused reversely at 76mmHg with KH solution at 37℃and gased with 95%O2-5%CO2. After balancing for 30 min, the left ventricular developed pressure was recorded as the basal value. After preservation for certain time periods, the hearts were reloaded onto the Langendorff perfusion apparatus and reperfused for another 60 min. LVDP was recorded during reperfusion.
(2) Cell apoptosis assay:At the end of reperfusion, the cardiac apex of the left ventricle was used. Cell apoptosis was detected by TUNEL assay.
(3) The expression of Bid:At the end of reperfusion, the cardiac apex of the left ventricle was used. The protein expression of Bid and tBid were assessed by Western Blot.
(4) The expression of Hsp90:At the end of reperfusion, the cardiac apex of the left ventricle was used. The mRNA expression of Hsp90 was assessed by RT-PCR and the protein expression was detected by Westren Blot.
Results
(1) Compared with control group, LVDP recovery rate significantly decreased and cardiomyocyte apoptosis index increased after 3-9 h of hypothermic preservation in a time dependent manner. When compared with the 9 h preservation group, supplement Celsior solution with diazoxide significantly (30μM) enhanced the LVDP recovery rate and decreased the apoptosis index.
(2) The cleavage of Bid increased after 9 h of hypothemic preservation, which was inhibited by supplying Celsior solution with diazoxide.
(3) Compared with control group, hypothermic preservation of rat hearts for 3 h increased the expression of Hsp90 mRNA and protein. But, the expression of Hsp90 mRNA and protein was decreased when the hypothermic preservation time was prolonged to 6-9 h. After supplement with diazoxide, the expression of Hsp90 mRNA and protein was significantly increased in 9 h preserved rat hearts.
(4) Hsp90 inhibitor 17-AAG inhibited the diazoxide-induced decrease in tBid. Meanwhile,17-AAG also partly abolished the diazoxide-induced improvement of cardiac function and decrease of apoptosis.
Conclusion Hsp90 might mediate diazoxide-induced cardioprotection against apoptosis in hypothermic preservation heart by preventing the cleavage of Bid.
心脏移植是一种用于治疗严重冠心病等终末期心脏病患者的有效的外科手段,成功的器官保存是心脏移植手术成功的必要前提。然而,目前临床上心脏的低温保存时间局限在4至6h以内,这与其它器官如肝、肾、胰的保存时间相比要短的多。如何有效地延长供心的保存时间是当前迫切需要解决的问题。研究发现在Celsior心脏保存液中添加二氮嗪,能促进长时低温保存后心功能的恢复并减少心肌细胞凋亡。热休克蛋白90(Heat shock protein 90,Hsp90)是一类高度保守的蛋白质家族的成员之一。Hsp90表达增加可诱导细胞保护作用,其机制被认为与其抗凋亡作用相关。然而,Hsp90是否参与了二氮嗪对抗低温保存诱导的心肌细胞凋亡作用尚不明了。
目的
研究Hsp90是否参与了二氮嗪对抗低温保存诱导的心功能下降,同时探究其可能机制。
方法
(1)低温保存模型的建立及心功能测定：离体大鼠心脏于Langendorff恒压灌注装置上平衡后,经主动脉根部灌注40C的Celsior'心麻痹液,灌注时间控制在3min以内,心脏表面同时降温,待心脏停跳后分别置于不同成分的心麻痹液中(4℃)保存,3、6、或9h后心脏被重新置于Langendorff装置上再灌注60min。灌注条件同保存前保持一致。通过MedLab生物信号采集处理系统观察左心室发展压(LVDP)。
(2)细胞凋亡测定：取复灌末期大鼠左心室心尖部分,用TUNEL法观察细胞凋亡情况。计算阳性凋亡细胞占总细胞数的百分比即为细胞凋亡指数(apoptosis index,AI)
(3)Bid表达：取复灌末期大鼠心脏左心室心尖部分,匀浆提蛋白,用Western Blot来检测Bid和tBid蛋白表达情况。
(4)Hsp90表达：取复灌末期大鼠心脏左心室心尖部分,用RT-PCR检测Hsp90mRNA水平,用Western Blot来检测Hsp90蛋白质水平
结果
(1)心脏于单纯Celsior保存液中低温保存3-9 h后,于复灌60 min末测得各组心脏LVDP'恢复率随着保存时间的延长而逐渐降低,心肌细胞凋亡指数随着保存时间的延长而逐渐升高。而与单纯Celsior保存液组相比,心脏在添加了二氮嗪(30μtM)的保存液中保存9h后LVDP'恢复率显著增高,心肌细胞凋亡指数显著下降。
(2)心脏于单纯Celsior保存液中低温保存3h后,Bid蛋白表达量与对照组无明显差异,且无明显裂解。低温保存6h或9h后,Bid裂解后产生的tBid(truncated Bid)片段量显著增加；然而,在心脏保存液中添加二氮嗪后,Bid裂解明显受抑制。
(3)与对照组相比,心脏于Celsior液低温保存3h,Hsp90 mRNA与蛋白表达水平均明显增加。但随着保存时间延长至6-9 h,Hsp90 mRNA与蛋白表达水平却逐渐降低。与9h单纯保存液组相比,二氮嗪组心脏Hsp90 mRNA与蛋白表达水平均显著提高。
(4)17-AAG可部分取消二氮嗪增加低温保存心脏LVDP恢复率的作用。此外,与二氮嗪组相比,保存液中同时添加17-AAG和二氮嗪,Bid裂解产物tBid含量显著增加,心肌细胞凋亡显著增加。
结论二氮嗪可抑制低温保存诱导的心肌细胞Bid蛋白裂解与细胞凋亡,其机制可能与Hsp90表达增加有关。
Background
Heart transplantation is a surgical transplant procedure performed on patients with end-stage heart failure or severe coronary artery disease. Successful organ preservation is the premise for clinical organ transplantation. However, hypothermic preservation of the heart has a limit of about 4-6 h, which is much lower than that for the liver, kidney, and pancreas.Prolonged donor heart preservation becomes more important in cardiovascular surgery. We have reported that diazoxide as a supplementation in Celsior preservation solution, can improve myocardial function and decrease apoptosis during long- term hypothermic preservation. However, the exact anti-apoptotic mechanism of diazoxide is still unknown. The heat shock proteins (Hsps) are highly conserved families of proteins, the cytoprotective function of Hsp90 is largely explained by their anti-apoptotic function, since Hsp90 has been shown to interact with different key apoptotic proteins.
Objectives
To investigate whether heat shock protein 90 (Hsp90) plays an important role in the anti-apoptotic effect of diazoxide in hypothermic preservation rat hearts.
Methods
(1) In vitro hypothermic heart preservation model and cardiac function assay: Male SD rat hearts were quickly removed and washed in cold Krebs-Henseleit (KH) solution. Then hearts were mounted on the Langendorff perfusion apparatus, and perfused reversely at 76mmHg with KH solution at 37℃and gased with 95%O2-5%CO2. After balancing for 30 min, the left ventricular developed pressure was recorded as the basal value. After preservation for certain time periods, the hearts were reloaded onto the Langendorff perfusion apparatus and reperfused for another 60 min. LVDP was recorded during reperfusion.
(2) Cell apoptosis assay:At the end of reperfusion, the cardiac apex of the left ventricle was used. Cell apoptosis was detected by TUNEL assay.
(3) The expression of Bid:At the end of reperfusion, the cardiac apex of the left ventricle was used. The protein expression of Bid and tBid were assessed by Western Blot.
(4) The expression of Hsp90:At the end of reperfusion, the cardiac apex of the left ventricle was used. The mRNA expression of Hsp90 was assessed by RT-PCR and the protein expression was detected by Westren Blot.
Results
(1) Compared with control group, LVDP recovery rate significantly decreased and cardiomyocyte apoptosis index increased after 3-9 h of hypothermic preservation in a time dependent manner. When compared with the 9 h preservation group, supplement Celsior solution with diazoxide significantly (30μM) enhanced the LVDP recovery rate and decreased the apoptosis index.
(2) The cleavage of Bid increased after 9 h of hypothemic preservation, which was inhibited by supplying Celsior solution with diazoxide.
(3) Compared with control group, hypothermic preservation of rat hearts for 3 h increased the expression of Hsp90 mRNA and protein. But, the expression of Hsp90 mRNA and protein was decreased when the hypothermic preservation time was prolonged to 6-9 h. After supplement with diazoxide, the expression of Hsp90 mRNA and protein was significantly increased in 9 h preserved rat hearts.
(4) Hsp90 inhibitor 17-AAG inhibited the diazoxide-induced decrease in tBid. Meanwhile,17-AAG also partly abolished the diazoxide-induced improvement of cardiac function and decrease of apoptosis.
Conclusion Hsp90 might mediate diazoxide-induced cardioprotection against apoptosis in hypothermic preservation heart by preventing the cleavage of Bid.
引文
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60. Frebel, K. and S. Wiese, Signalling molecules essential for neuronal survival and differentiation. Biochem Soc Trans,2006.34(Pt 6):p.1287-90.
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63. Pandey, P., et al., Negative regulation of cytochrome c-mediated oligomerization of Apaf-1 and activation of procaspase-9 by heat shock protein 90. EMBO J, 2000.19(16):p.4310-22.