亚低温诱导MKP-1保护TNF-α引起的内皮细胞屏障功能紊乱和凋亡
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摘要
研究背景和目的：
临床研究表明亚低温疗法(32-34℃)在中风、脑损伤、心脏骤停等多种疾病中具有显著的保护作用。而血管内皮与许多病理过程的发生发展关系密切。然而,迄今为止,亚低温在各种原因引起的内皮细胞损伤中能否起到保护作用以及其中的作用机制尚不明确。因此,本研究拟探讨亚低温在肿瘤坏死因子-α(tumor necrosis factor-alpha, TNF-α)引起的内皮细胞屏障功能紊乱和凋亡中的作用及其中的分子机理。
实验方法：
用TNF-α处理人脐静脉内皮细胞(human umbilical vein endothelial cells, HUVECs),再分别放置于正常温度(37℃)和亚低温(33℃)培养箱中培养2-6小时。用异硫氰酸荧光素标记的牛血清白蛋白(FITC-BSA)体外通透性实验检测单层内皮细胞的通透性、用罗丹明标记的鬼笔环肽染色法检测细胞内纤维状的肌动蛋白(F-肌动蛋白)骨架、用原位末端标记(terminal dUTP nick-end labeling, TUNEL)染色法检测细胞的凋亡。用免疫印记(western blot)法检测半胱氨酸蛋白水解酶-3片段(Cleaved caspaspe-3, Asp175)、丝裂原活化蛋白激酶(mitogen-activated protein kinase, MAPK) p38、c-Jun氨基末端激酶(c-Jun N-terminal kinase, JNK)、热休克蛋白27 (heat shock protein 27, HSP27)、c-Jun、MAPK激酶3/6 (MAPK kinase3/6, MKK3/6)、MAPK激酶7 (MAPK kinase7, MKK7)和MAPK磷酸酶-1(MAPK phosphatase-1, MKP-1)的蛋白表达；另外,用p38 MAPK特异性抑制剂SB203580或者JNK特异性抑制剂SP600125预处理HUVECs,再进行TNF-α处理,并对上述各项指标进行检测；同时,将HUVECs不加任何刺激剂放置于亚低温培养箱中培养,再检测MKP-1的蛋白水平和mRNA水平以及p38 MAPK和JNK的蛋白表达；最后用MKP-1的siRNA转染HUVECs,再进行TNF-α处理,同时检测各项指标。
实验结果：
(1)TNF-α处理引起单层HUVECs通透性显著增强、细胞肌动蛋白骨架重排、和凋亡发生,而亚低温能显著抑制TNF-α引起的这些内皮损伤效应。
(2)亚低温抑制TNF-α活化的p38 MAPK和JNK信号通路。
(3)亚低温通过抑制p38 MAPK/HSP27信号通路减弱TNF-α引起的内皮细胞肌动蛋白骨架的重排和压力纤维的形成。
(4)亚低温对内皮细胞凋亡的保护作用是通过抑制p38 MAPK和JNK信号通路而实现的。
(5)亚低温对p38 MAPK和JNK的上游激酶MKK3／6和MKK7无明显影响,但可显著上调p38 MAPK和JNK的上游磷酸酶MKP-1。
(6) siRNA实验表明,亚低温通过诱导MKP-1的表达抑制TNF-a引起的p38MAPK和JNK信号通路的激活以及内皮细胞屏障功能紊乱和凋亡
结论：
亚低温通过诱导MKP-1的表达,抑制TNF-a引起的p38 MAPK和JNK信号通路的激活,从而保护TNF-a引起的内皮细胞屏障功能紊乱和凋亡。
Aims:Hypothermia therapy has been shown to confer robust protection against numerous diseases inclusing stroke, brain injury, and cardiac arrest, and vascular endothelial cells are involved in stress-induced pathogenesis under insult conditions. However, the mechanisms underlying protective effect of mild hypothermia on endothelial cells have not yet been completely elucidated. Here, we investigated molecular effects of mild hypothermia on tumor necrosis factor-alpha (TNF-α)-induced endothelial barrier dysfunction and apoptosis.
Methods:Human umbilical vein endothelial cells (HUVECs) treated with TNF-a were incubated under normothermia (37℃) or mild hypothermia (33℃). Endothelial permeability was detemined by fluorescein-isothiocyanate-labeled bovine serum albumin (FITC-BSA); actin cytoskeleton alterations was stained and tested with rhodamine-phalloidin; apoptosis was examined by terminal dUTP nick-end labeling (TUNEL) assay; the protein levels were determined by immunoblot. Then, the cells were transfected with MKP-1 siRNA, and were treated with TNF-α. The former detections were also performed.
Results:
(1) Treatment of HUVECs with TNF-αresulted in a significant increase of nomo-endothelial permeability, actin reorganization and apoptosis. Mild hypothermia markedly attenuated TNF-α-induced these effects.
(2) Mild hypothermia inhibits TNF-α-induced activation of p38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase (JNK) pathways.
(3) The inhibitory action of mild hypothermia on stress fiber formation was mediated via inactivation of p38 MAPK/heat shock protein 27 (HSP27).
(4) The decrease in TNF-α-induced apoptosis by mild hypothermia was associated with inhibition of p38 MAPK and JNK activity.
(5) Mild hypothermia had no action on p38 MAPK and JNK upstream kinases MAPK kinase 3/6 (MKK3/6) and MAPK kinase 7 (MKK7), but markedly induced the expression of MAPK phosphatase-1 (MKP-1).
(6) siRNA experiments showed that MKP-1 was an important mediator of mild hypothermia in attenuatting TNF-α-induced activation of p38 MAPK and JNK, endothelial barrier dysfunction, and apoptosis in HUVECs.
Conclusion:These results for the first time demonstrate that mild hypothermia protects against TNF-α-induced endothelial barrier dysfunction and apoptosis through MKP-1-dependent mechanism.
临床研究表明亚低温疗法(32-34℃)在中风、脑损伤、心脏骤停等多种疾病中具有显著的保护作用。而血管内皮与许多病理过程的发生发展关系密切。然而,迄今为止,亚低温在各种原因引起的内皮细胞损伤中能否起到保护作用以及其中的作用机制尚不明确。因此,本研究拟探讨亚低温在肿瘤坏死因子-α(tumor necrosis factor-alpha, TNF-α)引起的内皮细胞屏障功能紊乱和凋亡中的作用及其中的分子机理。
实验方法：
用TNF-α处理人脐静脉内皮细胞(human umbilical vein endothelial cells, HUVECs),再分别放置于正常温度(37℃)和亚低温(33℃)培养箱中培养2-6小时。用异硫氰酸荧光素标记的牛血清白蛋白(FITC-BSA)体外通透性实验检测单层内皮细胞的通透性、用罗丹明标记的鬼笔环肽染色法检测细胞内纤维状的肌动蛋白(F-肌动蛋白)骨架、用原位末端标记(terminal dUTP nick-end labeling, TUNEL)染色法检测细胞的凋亡。用免疫印记(western blot)法检测半胱氨酸蛋白水解酶-3片段(Cleaved caspaspe-3, Asp175)、丝裂原活化蛋白激酶(mitogen-activated protein kinase, MAPK) p38、c-Jun氨基末端激酶(c-Jun N-terminal kinase, JNK)、热休克蛋白27 (heat shock protein 27, HSP27)、c-Jun、MAPK激酶3/6 (MAPK kinase3/6, MKK3/6)、MAPK激酶7 (MAPK kinase7, MKK7)和MAPK磷酸酶-1(MAPK phosphatase-1, MKP-1)的蛋白表达；另外,用p38 MAPK特异性抑制剂SB203580或者JNK特异性抑制剂SP600125预处理HUVECs,再进行TNF-α处理,并对上述各项指标进行检测；同时,将HUVECs不加任何刺激剂放置于亚低温培养箱中培养,再检测MKP-1的蛋白水平和mRNA水平以及p38 MAPK和JNK的蛋白表达；最后用MKP-1的siRNA转染HUVECs,再进行TNF-α处理,同时检测各项指标。
实验结果：
(1)TNF-α处理引起单层HUVECs通透性显著增强、细胞肌动蛋白骨架重排、和凋亡发生,而亚低温能显著抑制TNF-α引起的这些内皮损伤效应。
(2)亚低温抑制TNF-α活化的p38 MAPK和JNK信号通路。
(3)亚低温通过抑制p38 MAPK/HSP27信号通路减弱TNF-α引起的内皮细胞肌动蛋白骨架的重排和压力纤维的形成。
(4)亚低温对内皮细胞凋亡的保护作用是通过抑制p38 MAPK和JNK信号通路而实现的。
(5)亚低温对p38 MAPK和JNK的上游激酶MKK3／6和MKK7无明显影响,但可显著上调p38 MAPK和JNK的上游磷酸酶MKP-1。
(6) siRNA实验表明,亚低温通过诱导MKP-1的表达抑制TNF-a引起的p38MAPK和JNK信号通路的激活以及内皮细胞屏障功能紊乱和凋亡
结论：
亚低温通过诱导MKP-1的表达,抑制TNF-a引起的p38 MAPK和JNK信号通路的激活,从而保护TNF-a引起的内皮细胞屏障功能紊乱和凋亡。
Aims:Hypothermia therapy has been shown to confer robust protection against numerous diseases inclusing stroke, brain injury, and cardiac arrest, and vascular endothelial cells are involved in stress-induced pathogenesis under insult conditions. However, the mechanisms underlying protective effect of mild hypothermia on endothelial cells have not yet been completely elucidated. Here, we investigated molecular effects of mild hypothermia on tumor necrosis factor-alpha (TNF-α)-induced endothelial barrier dysfunction and apoptosis.
Methods:Human umbilical vein endothelial cells (HUVECs) treated with TNF-a were incubated under normothermia (37℃) or mild hypothermia (33℃). Endothelial permeability was detemined by fluorescein-isothiocyanate-labeled bovine serum albumin (FITC-BSA); actin cytoskeleton alterations was stained and tested with rhodamine-phalloidin; apoptosis was examined by terminal dUTP nick-end labeling (TUNEL) assay; the protein levels were determined by immunoblot. Then, the cells were transfected with MKP-1 siRNA, and were treated with TNF-α. The former detections were also performed.
Results:
(1) Treatment of HUVECs with TNF-αresulted in a significant increase of nomo-endothelial permeability, actin reorganization and apoptosis. Mild hypothermia markedly attenuated TNF-α-induced these effects.
(2) Mild hypothermia inhibits TNF-α-induced activation of p38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase (JNK) pathways.
(3) The inhibitory action of mild hypothermia on stress fiber formation was mediated via inactivation of p38 MAPK/heat shock protein 27 (HSP27).
(4) The decrease in TNF-α-induced apoptosis by mild hypothermia was associated with inhibition of p38 MAPK and JNK activity.
(5) Mild hypothermia had no action on p38 MAPK and JNK upstream kinases MAPK kinase 3/6 (MKK3/6) and MAPK kinase 7 (MKK7), but markedly induced the expression of MAPK phosphatase-1 (MKP-1).
(6) siRNA experiments showed that MKP-1 was an important mediator of mild hypothermia in attenuatting TNF-α-induced activation of p38 MAPK and JNK, endothelial barrier dysfunction, and apoptosis in HUVECs.
Conclusion:These results for the first time demonstrate that mild hypothermia protects against TNF-α-induced endothelial barrier dysfunction and apoptosis through MKP-1-dependent mechanism.
引文
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