抵抗素对人脐静脉内皮细胞组织因子及其途径抑制物表达的调节
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摘要
背景
近年来以中心性肥胖、胰岛素抵抗为主要特征的代谢综合征(metabolic syndrome, MetS)发病率逐年升高。代谢综合征患者处于血栓前状态,直接增加动静脉血栓发病风险,但发病机制尚未完全阐明。组织因子(tissue factor, TF)是外源性凝血启动的关键因子,组织因子途径抑制物(tissue factor pathway inhibitor, TFPI)是目前发现的体内最强的生理性抗凝物质,是TF直接的生理性抑制物,在调节TF诱导的血栓形成中发挥重要作用。本实验观察脂肪细胞因子之一的抵抗素(resistin, R)对TF及TFPI的调节作用,从对凝血与抗凝系统活性因子的调节角度探讨代谢综合征患者易患血栓性疾病的原因及机制。
目的
体外培养人脐静脉内皮细胞(human umbilical vein endothelial cells, HUVECs),观察不同浓度不同时间抵抗素处理后TF和TFPI蛋白及mRNA表达的变化,并探讨抵抗素是否能够通过细胞外信号调节激酶(extracellular signal-regulated kinases, ERK)、c-Jun氨基末端激酶(the c-Jun NH2-terminal kinases, JNKs)及丝裂原活化蛋白激酶p38(p38 MAPK)通路来调节人脐静脉内皮细胞TFPI的表达。
方法
(1)将体外培养的4-5代人脐静脉内皮细胞(HUVECs)分为单纯培养基对照组、不同浓度抵抗素(10ng/mL、25ng/mL、50ng/mL、100ng/mL)组,培养48h后,1)MTT法检测细胞活性;2)ELISA法测各组细胞裂解产物中的TF蛋白含量及上清液中总TFPI蛋白含量,real-time RT-PCR检测各组TF mRNA及TFPI mRNA表达;
(2)将HUVECs 4-5代分为单纯培养基对照组、抵抗素(50ng/mL)组、ERK磷酸化抑制剂PD98059(10μmol/L)组、JNK磷酸化抑制剂SP600125(2.5μmol/L)组、p38磷酸化抑制剂SB20358(010μmol/L)组及各组抑制剂预处理组,分别培养48h后用ELISA法测各组细胞上清液中总TFPI蛋白含量。
结果
(1)各浓度抵抗素对HUVECs的细胞活力没有明显影响(p>0.05);(2)25ng/mL及50ng/mL抵抗素在6h可显著增加TF蛋白的水平(p<0.05),以50ng/mL作用最显著,24h和48h没有明显影响(p>0.05),50ng/mL抵抗素对HUVECs表达TF mRNA无明显作用(p>0.05);(3)50ng/mL抵抗素在24h,25ng/mL、50ng/mL及100ng/mL抵抗素在48h可显著降低TFPI蛋白水平(p<0.05),以48h 50ng/mL作用最显著,但50ng/mL抵抗素对TFPI mRNA表达无明显影响(p>0.05);(4)ERK、JNK、p38抑制剂预处理组TFPI蛋白水平与50ng/mL抵抗素单独作用组相比无明显升高。
结论
抵抗素可通过增加HUVECs的TF蛋白表达,抑制TFPI蛋白的水平,促进血栓形成;但不是通过对TF、TFPI基因表达水平的调节实现的,其具体调控机制有待进一步研究。
Background
The prevalence of the metabolic syndrome ( MetS ), a concurrence of abdominal fat and insulin resistance, has been rising during recent years. Metabolic syndrome induced a pro-thrombotic state and was closely associated with an increased risk of arterial and venous thromboembolism. The mechanism, however, has not been fully elucidated. Tissue factor ( TF ) is a key initiator in the activation of extrinsic coagulation while tissue factor pathway inhibitor ( TFPI ) is found to be the strongest physiological anticoagulant substances in vivo and is a specific and only physiological inhibitor of TF that modulates the effect of TF-induced coagulation. In this study, we investigated whether resistin regulate the expression of TF and TFPI and to further explore the mechanism of metabolic syndrome in patients susceptible to thrombotic diseases.
Objective
To observe the direct effects of resistin on the TF and TFPI protein and their mRNA levels in cultured human umbilical vein endothelial cells ( HUVECs ). Then to study the cellular mechanism to investigate whether the extracellular signal-regulated kinases ( ERK ), the c-Jun NH2-terminal kinases ( JNK ) or p38 signaling pathway are associated in the regulating process of ressitin on TFPI.
Methods
( 1 ) HUVECs within 4-5 passages were divided into 5 experimental groups: controls ( medium only ), different concentrations resistin treated group ( 10ng/mL, 25ng/mL, 50ng/mL, 100ng/mL ). After incubation for 48h, 1 ) the activities of cells were detected by MTT assay; 2 ) the antigen levels of TF and TFPI were assessed with an enzyme-linked immunosorbent assay ( ELISA ), and mRNA levels were detected by real-time RT-PCR.
( 2 ) HUVECs within 4-5 passages were divided into: culture medium only group ( control ), 50ng/mL resistin treated group, ERK inhibitor PD98059 treated group ( 10μmol/L ), PD98059 pretreated group ( PD + R ), JNK inhibitor SP600125 treated group ( 2.5μmol/L ), SP600125 pretreated group ( SP + R ), p38 inhibitor SB203580 treated group ( 10μmol/L ), SB203580 pretreated group ( SB + R ). After incubation for 48h, TFPI antigen levels were analyzed with ELISA kit.
Results
( 1 ) Incubation with resistin ( 10ng/mL, 25ng/mL, 50ng/mL, 100ng/ml ) didn’t affect HUVECs proliferation and viability ( p>0.05 ); ( 2 ) 25ng/mL and 50ng/mL resistin markedly up-regulated TF protein expression at 6h ( p<0.05 ), and the most effective regulation was the 50ng/mL resistin. While no significant effect was found at 24h or at 48h ( p>0.05 for both ). TF mRNA was not changed significantly with the 50ng/mL resistin infusion ( p>0.05 ); ( 3 ) 50ng/mL resistin at 24h, 25ng/mL, 50ng/mL and 100ng/mL resistin at 48h reduced TFPI protein levels ( p<0.05 ), and the most effective regulation was 50ng/mL resistin at 48h. Resistin did not influence the mRNA levels of TFPI ( p>0.05 ); ( 4 )After HUVECs preteated with ERK inhibitor PD98059, JNK inhibitor SP600125 or p38 inhibitor SB203580, no significant increase was observed in the expression of TFPI antigen between pretreated groups and 50ng/mL resistin only trested HUVECs.
Conclusion
Human recombined resistin induced increased TF, and reduction of TFPI levels in cultured HUVECs possibly due to a post-transcriptional regulational mechanism, suggesting a potential pathophysiology role of resistin to aggregate the thrombosis development. The signaling pathway, however, needs further investigation.
近年来以中心性肥胖、胰岛素抵抗为主要特征的代谢综合征(metabolic syndrome, MetS)发病率逐年升高。代谢综合征患者处于血栓前状态,直接增加动静脉血栓发病风险,但发病机制尚未完全阐明。组织因子(tissue factor, TF)是外源性凝血启动的关键因子,组织因子途径抑制物(tissue factor pathway inhibitor, TFPI)是目前发现的体内最强的生理性抗凝物质,是TF直接的生理性抑制物,在调节TF诱导的血栓形成中发挥重要作用。本实验观察脂肪细胞因子之一的抵抗素(resistin, R)对TF及TFPI的调节作用,从对凝血与抗凝系统活性因子的调节角度探讨代谢综合征患者易患血栓性疾病的原因及机制。
目的
体外培养人脐静脉内皮细胞(human umbilical vein endothelial cells, HUVECs),观察不同浓度不同时间抵抗素处理后TF和TFPI蛋白及mRNA表达的变化,并探讨抵抗素是否能够通过细胞外信号调节激酶(extracellular signal-regulated kinases, ERK)、c-Jun氨基末端激酶(the c-Jun NH2-terminal kinases, JNKs)及丝裂原活化蛋白激酶p38(p38 MAPK)通路来调节人脐静脉内皮细胞TFPI的表达。
方法
(1)将体外培养的4-5代人脐静脉内皮细胞(HUVECs)分为单纯培养基对照组、不同浓度抵抗素(10ng/mL、25ng/mL、50ng/mL、100ng/mL)组,培养48h后,1)MTT法检测细胞活性;2)ELISA法测各组细胞裂解产物中的TF蛋白含量及上清液中总TFPI蛋白含量,real-time RT-PCR检测各组TF mRNA及TFPI mRNA表达;
(2)将HUVECs 4-5代分为单纯培养基对照组、抵抗素(50ng/mL)组、ERK磷酸化抑制剂PD98059(10μmol/L)组、JNK磷酸化抑制剂SP600125(2.5μmol/L)组、p38磷酸化抑制剂SB20358(010μmol/L)组及各组抑制剂预处理组,分别培养48h后用ELISA法测各组细胞上清液中总TFPI蛋白含量。
结果
(1)各浓度抵抗素对HUVECs的细胞活力没有明显影响(p>0.05);(2)25ng/mL及50ng/mL抵抗素在6h可显著增加TF蛋白的水平(p<0.05),以50ng/mL作用最显著,24h和48h没有明显影响(p>0.05),50ng/mL抵抗素对HUVECs表达TF mRNA无明显作用(p>0.05);(3)50ng/mL抵抗素在24h,25ng/mL、50ng/mL及100ng/mL抵抗素在48h可显著降低TFPI蛋白水平(p<0.05),以48h 50ng/mL作用最显著,但50ng/mL抵抗素对TFPI mRNA表达无明显影响(p>0.05);(4)ERK、JNK、p38抑制剂预处理组TFPI蛋白水平与50ng/mL抵抗素单独作用组相比无明显升高。
结论
抵抗素可通过增加HUVECs的TF蛋白表达,抑制TFPI蛋白的水平,促进血栓形成;但不是通过对TF、TFPI基因表达水平的调节实现的,其具体调控机制有待进一步研究。
Background
The prevalence of the metabolic syndrome ( MetS ), a concurrence of abdominal fat and insulin resistance, has been rising during recent years. Metabolic syndrome induced a pro-thrombotic state and was closely associated with an increased risk of arterial and venous thromboembolism. The mechanism, however, has not been fully elucidated. Tissue factor ( TF ) is a key initiator in the activation of extrinsic coagulation while tissue factor pathway inhibitor ( TFPI ) is found to be the strongest physiological anticoagulant substances in vivo and is a specific and only physiological inhibitor of TF that modulates the effect of TF-induced coagulation. In this study, we investigated whether resistin regulate the expression of TF and TFPI and to further explore the mechanism of metabolic syndrome in patients susceptible to thrombotic diseases.
Objective
To observe the direct effects of resistin on the TF and TFPI protein and their mRNA levels in cultured human umbilical vein endothelial cells ( HUVECs ). Then to study the cellular mechanism to investigate whether the extracellular signal-regulated kinases ( ERK ), the c-Jun NH2-terminal kinases ( JNK ) or p38 signaling pathway are associated in the regulating process of ressitin on TFPI.
Methods
( 1 ) HUVECs within 4-5 passages were divided into 5 experimental groups: controls ( medium only ), different concentrations resistin treated group ( 10ng/mL, 25ng/mL, 50ng/mL, 100ng/mL ). After incubation for 48h, 1 ) the activities of cells were detected by MTT assay; 2 ) the antigen levels of TF and TFPI were assessed with an enzyme-linked immunosorbent assay ( ELISA ), and mRNA levels were detected by real-time RT-PCR.
( 2 ) HUVECs within 4-5 passages were divided into: culture medium only group ( control ), 50ng/mL resistin treated group, ERK inhibitor PD98059 treated group ( 10μmol/L ), PD98059 pretreated group ( PD + R ), JNK inhibitor SP600125 treated group ( 2.5μmol/L ), SP600125 pretreated group ( SP + R ), p38 inhibitor SB203580 treated group ( 10μmol/L ), SB203580 pretreated group ( SB + R ). After incubation for 48h, TFPI antigen levels were analyzed with ELISA kit.
Results
( 1 ) Incubation with resistin ( 10ng/mL, 25ng/mL, 50ng/mL, 100ng/ml ) didn’t affect HUVECs proliferation and viability ( p>0.05 ); ( 2 ) 25ng/mL and 50ng/mL resistin markedly up-regulated TF protein expression at 6h ( p<0.05 ), and the most effective regulation was the 50ng/mL resistin. While no significant effect was found at 24h or at 48h ( p>0.05 for both ). TF mRNA was not changed significantly with the 50ng/mL resistin infusion ( p>0.05 ); ( 3 ) 50ng/mL resistin at 24h, 25ng/mL, 50ng/mL and 100ng/mL resistin at 48h reduced TFPI protein levels ( p<0.05 ), and the most effective regulation was 50ng/mL resistin at 48h. Resistin did not influence the mRNA levels of TFPI ( p>0.05 ); ( 4 )After HUVECs preteated with ERK inhibitor PD98059, JNK inhibitor SP600125 or p38 inhibitor SB203580, no significant increase was observed in the expression of TFPI antigen between pretreated groups and 50ng/mL resistin only trested HUVECs.
Conclusion
Human recombined resistin induced increased TF, and reduction of TFPI levels in cultured HUVECs possibly due to a post-transcriptional regulational mechanism, suggesting a potential pathophysiology role of resistin to aggregate the thrombosis development. The signaling pathway, however, needs further investigation.
引文
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