褪黑素对体外培养的脐静脉内皮细胞增殖和凋亡的影响
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摘要
褪黑素对体外培养的脐静脉内皮细胞增殖和凋亡的影响
目的：第一部分：为了探讨褪黑素(MEL)在血管新生方面的作用和可能的抗肿瘤血管新生机制，以体外培养的脐静脉内皮细胞(HUVECs)为模型，观察MEL对HUVECs增殖和凋亡的影响。第二部分：在第一部分基础上，探讨高浓度MEL抑制HUVECs增殖和促其凋亡的可能细胞信号传导通路。
方法：第一部分：原代培养HUVECs，免疫磁珠筛选后，并用免疫组化和电镜鉴定内皮细胞；MTT法测定不同浓度的MEL对HUVECs增殖的影响，并用流式细胞仪测定HUVECs细胞周期和细胞凋亡情况；免疫荧光、Western Blot和RT-PCR检测MEL对HUVECs内凋亡相关蛋白P53、Bcl-2和Bax及其基因表达情况。第二部分：在第一部分基础上，RT-PCR检测HUVECs褪黑素膜受体和核受体(MELR和RZR／ROR)的表达情况，以及MEL对其表达影响；检测高浓度MEL对影响HUVECs增殖和凋亡的重要的细胞内信号通路RTK／ERK／P13K／AKT／PKC／NF-κB蛋白表达影响；应用MELR受体阻滞剂Luzindole、ERK1／2激活抑制剂U0126、PI3K／AKT抑制剂LY294002以及PKC激活剂PMA和抑制剂GF 109203X，观察其对高浓度MEL抑制HUVECs增殖和相关细胞信号传递通路的影响。
结果：第一部分：(1)成功的分离培养原代HUVECs，免疫磁珠筛选后能继续贴壁生长并传代，倒置显微镜下HUVECs呈鹅卵石状，Ⅷ因子内皮细胞细胞免疫化学着棕色，电镜下可见内皮细胞特征性的Weibel-Palade小体。(2)极低浓度MEL(lnmol／L)对HUVECs增殖无明显影响，但高浓度MEL(10nmol／L-1mmol／L)明显抑制HUVECs增殖，并有浓度依赖倾向，1mmol／L抑制作用最明显。(3)流式细胞仪显示高浓度MEL能明显阻滞HUVECs细胞周期，能阻止细胞进入S期，引起“S期停滞”；凋亡分析显示高浓度的MEL能明显促使HUVECs凋亡，1mmol／L时最明显。(4)高浓度MEL(100nmol／L和lmmol／L)明显调节凋亡相关基因P53、Bax和Bcl-2的表达。(5)Western Blot和免疫荧光检测高浓度MEL促进HUVECs凋亡与细胞内P53和Bax蛋白表达上调，Bcl-2蛋白下调有关。
第二部分：(1)正常HUVECs中褪黑素膜受体MELlaR和MELlbR都有明显表达，而核受体家族中有RORa和RORb表达，以RORb表达更为突出，RORC几乎无表达。(2) MEL受体参与MEL抑制HUVECs增殖机制，膜受体阻滞剂Luzindole只能部分阻断高浓度MEL的增殖抑制效应。(3)外源性MEL可使HUVECs上MEL受体表达下调，此过程可能与PKCα表达上调有关。(4) ERK1／2、PI3K／AKT和PKC信号通路与HUVECs增殖密切相关，其特异的通路抑制剂能明显抑制HUVECs增殖。(5)高浓度MEL通过抑制ERK1／2、PI3K／AKT和PKC信号通路抑制了HUVECs增殖和促其凋亡，相应的通路抑制剂或激活剂能分别部分促进或阻断MEL抑制HUVECs增殖效应。(6) MEL抑制HUVECs中NF-κB的表达并抑制其和DNA结合，从而抑制HUVECs增殖和促其凋亡。(7)特异的ERK1／2、PI3K／AKT和PKC信号通路抑制剂能不同程度的阻断HUVECs中NF-κB的活性，和MEL作用类似，说明MEL可通过抑制ERK1／2、PI3K／AKT和PKC信号通路抑制NF-κB的活性，从而影响细胞增殖和凋亡。
结论：(1)高浓度的MEL能明显抑制HUVECs增殖和促其凋亡；(2)高浓度的MEL抑制HUVECs的增殖和促其凋亡与P53和Bax／Bc1-2基因和蛋白的表达改变密切相关；(3)高浓度MEL抑制HUVECs的增殖和促其凋亡可能与MEL受体、PI3K／AKT／ERK／PKC／NF-κB等多条信号途径密切相关。
Effect and mechanism of melatonin's action on the proliferation and apotosis in human umbilical vein cells
Objecive Part one: At present there are no direct data available as to melatonin's possible influence on angiogenesis, which is a major biological mechanism responsible for tumor growth and dissemination. The current study investigated the influence of melatonin on angiogenesis, and the action on the cell proliferation and apoptosis in human umbilical vein cells (HUVECs). Part two: on the basis of previous study, this study was designed to explore the possible cell signalling pathways when melatonin inhibited the HUVECs proliferation and induced apoptosis.
Methods Part one: Primary HUVECs were isolated from fresh human umbilical veins and cultured, after immunomagnetic separation by anti-CD31 antibody coated Dynabeads, the HUVECs were indentified by FactorⅧimmuocytochemical staining and eletroscope observation; MTT method was carried out to assay the proliferation of HUVECs when treated with melatonin in concentrations from 0.1nmol/L to 1mmol/L (final concetration in the medium); and the cell cycle and apoptosis were detect using propidium iodione (PI) staining; the expressions of P53, Bax and Bcl-2 mRNA were detected by RT-PCR, also the proteins by immunofluorescence and Westem Blot anaysis. Part Two: the melatonin's receptors type expression in HUVECs was detected at first, and the interactions was observed when treated with melatonin; the possible intracellular signaling pathways include MAPK/ERK, PI3K/AKT and PKC were detected whether contributed to the anti-proliferative and pro-apoptotic effect of the indolamine in HUVECs by using specific inhibitors and activators; EMSA was used to detected the NF-κB binding activity in HUVECs when treated with melatonin and the relationship between NF-κB and its possible up-stream trigger signaling pathways.
Results Part one: (1) Primary HUVECs were isolated sucessfully from fresh human umbilical veins and cultured, afer purified by immunomagnetic separation. The endothelial origin was confirmed by the positive labeling of von Willebrand Factor (vWF), CD31 and electronmicropy observation. (2) At near physiological concentrations (1nmol/L), melatonin had no significant effect on cellular proliferation. However, melatonin in higher concentrations (greater than 10 nmol/L) significantly decreased cell proliferation, and the negative effect on HUVECs proliferation was enhanced with increasing melatonin concentrations. Melatonin of 1mmol/L had the greatest antiproliferative effect on HUVECs with the cell viability no difference between the control and the melatonin-treatment groups. (3) FCM showed HUVECs treated with melatonin in high concentrations presented a very distinct hypodiploid peak of apoptosis (0.64% vs 31.3%, P<0.01), and Cell cycle analyzed also showed a reduction of cells entering in the S phase (S phase arrest). (4) The Bax or P53 mRNA expression is increasing when treatment with 100nmol/L after 24hr, whereas no obvious changes to Bcl-2, but when incubated with 1mmol/L melatonin, a very early increasing expression of P53 and Bax mRNA at 3hr and a later decrease of Bcl-2 mRNA were shown. (4) The up-regulation of P53 and Bax and down-regulation of Bcl-2 proteins possibly contributed to the apoptotis in HUVECs with melatonin.
Part two: (1) In normal cultured HUVECs, G- protein- coupled membrane receptors of melatonin (MT1 and MT2) also with the nuclear receptors of melatonin (RORa and RORb, especially RORb) are both expressed, whereas no obvious expression of RORc in HUVECs. (2) The membrane receptors was involved in melatonin antiproliferative properties in HUVECs, and the receptor antagonist Luzindole could partially prevent the indolamine's efficacy. (3) In cultured HUVECs, melatonin, even at physiological concentrations, could suppress the expression of melatonin receptors, and it may be the outcome of a direct or indirect melatonin-mediated activation of constitutive PKCα. (4) The survival and proliferation of HUVECs is dependent on the activation of several intracellular signaling pathways include mitogen-activated protein kinases (MAPK)/extracellualar signal-related kinases (ERK), phosphoinositol-3-kinase (PI3K)/AKT and protein kinases C (PKC), and the blockade of these pathways by specifical inhibitors could decrease the cell growth rate respectively. (5) High concentration melatonin reduced the proliferation and induced the apoptosis direct or indirect by inactivation the ERK, PI3K/AKT and PKC, with the fact that the antiproliferative effect was partially regulated by its special inhibitors and activators. (6) HUVECs showed basal activation of NF-κB transcription factor, and high concetration melatonin inhibited the NF-κB expression and its binding to DNA. (7) All the signaling pathways specical inhibior could partially inhbit the NF-κB binding to DNA, thus suggest melatonin inhibited NF-κB activity possibly through inactivating these pathways, which may be responsible for the antiproliferative and pro-apoptotic effect of melatonin in HUVECs.
目的：第一部分：为了探讨褪黑素(MEL)在血管新生方面的作用和可能的抗肿瘤血管新生机制，以体外培养的脐静脉内皮细胞(HUVECs)为模型，观察MEL对HUVECs增殖和凋亡的影响。第二部分：在第一部分基础上，探讨高浓度MEL抑制HUVECs增殖和促其凋亡的可能细胞信号传导通路。
方法：第一部分：原代培养HUVECs，免疫磁珠筛选后，并用免疫组化和电镜鉴定内皮细胞；MTT法测定不同浓度的MEL对HUVECs增殖的影响，并用流式细胞仪测定HUVECs细胞周期和细胞凋亡情况；免疫荧光、Western Blot和RT-PCR检测MEL对HUVECs内凋亡相关蛋白P53、Bcl-2和Bax及其基因表达情况。第二部分：在第一部分基础上，RT-PCR检测HUVECs褪黑素膜受体和核受体(MELR和RZR／ROR)的表达情况，以及MEL对其表达影响；检测高浓度MEL对影响HUVECs增殖和凋亡的重要的细胞内信号通路RTK／ERK／P13K／AKT／PKC／NF-κB蛋白表达影响；应用MELR受体阻滞剂Luzindole、ERK1／2激活抑制剂U0126、PI3K／AKT抑制剂LY294002以及PKC激活剂PMA和抑制剂GF 109203X，观察其对高浓度MEL抑制HUVECs增殖和相关细胞信号传递通路的影响。
结果：第一部分：(1)成功的分离培养原代HUVECs，免疫磁珠筛选后能继续贴壁生长并传代，倒置显微镜下HUVECs呈鹅卵石状，Ⅷ因子内皮细胞细胞免疫化学着棕色，电镜下可见内皮细胞特征性的Weibel-Palade小体。(2)极低浓度MEL(lnmol／L)对HUVECs增殖无明显影响，但高浓度MEL(10nmol／L-1mmol／L)明显抑制HUVECs增殖，并有浓度依赖倾向，1mmol／L抑制作用最明显。(3)流式细胞仪显示高浓度MEL能明显阻滞HUVECs细胞周期，能阻止细胞进入S期，引起“S期停滞”；凋亡分析显示高浓度的MEL能明显促使HUVECs凋亡，1mmol／L时最明显。(4)高浓度MEL(100nmol／L和lmmol／L)明显调节凋亡相关基因P53、Bax和Bcl-2的表达。(5)Western Blot和免疫荧光检测高浓度MEL促进HUVECs凋亡与细胞内P53和Bax蛋白表达上调，Bcl-2蛋白下调有关。
第二部分：(1)正常HUVECs中褪黑素膜受体MELlaR和MELlbR都有明显表达，而核受体家族中有RORa和RORb表达，以RORb表达更为突出，RORC几乎无表达。(2) MEL受体参与MEL抑制HUVECs增殖机制，膜受体阻滞剂Luzindole只能部分阻断高浓度MEL的增殖抑制效应。(3)外源性MEL可使HUVECs上MEL受体表达下调，此过程可能与PKCα表达上调有关。(4) ERK1／2、PI3K／AKT和PKC信号通路与HUVECs增殖密切相关，其特异的通路抑制剂能明显抑制HUVECs增殖。(5)高浓度MEL通过抑制ERK1／2、PI3K／AKT和PKC信号通路抑制了HUVECs增殖和促其凋亡，相应的通路抑制剂或激活剂能分别部分促进或阻断MEL抑制HUVECs增殖效应。(6) MEL抑制HUVECs中NF-κB的表达并抑制其和DNA结合，从而抑制HUVECs增殖和促其凋亡。(7)特异的ERK1／2、PI3K／AKT和PKC信号通路抑制剂能不同程度的阻断HUVECs中NF-κB的活性，和MEL作用类似，说明MEL可通过抑制ERK1／2、PI3K／AKT和PKC信号通路抑制NF-κB的活性，从而影响细胞增殖和凋亡。
结论：(1)高浓度的MEL能明显抑制HUVECs增殖和促其凋亡；(2)高浓度的MEL抑制HUVECs的增殖和促其凋亡与P53和Bax／Bc1-2基因和蛋白的表达改变密切相关；(3)高浓度MEL抑制HUVECs的增殖和促其凋亡可能与MEL受体、PI3K／AKT／ERK／PKC／NF-κB等多条信号途径密切相关。
Effect and mechanism of melatonin's action on the proliferation and apotosis in human umbilical vein cells
Objecive Part one: At present there are no direct data available as to melatonin's possible influence on angiogenesis, which is a major biological mechanism responsible for tumor growth and dissemination. The current study investigated the influence of melatonin on angiogenesis, and the action on the cell proliferation and apoptosis in human umbilical vein cells (HUVECs). Part two: on the basis of previous study, this study was designed to explore the possible cell signalling pathways when melatonin inhibited the HUVECs proliferation and induced apoptosis.
Methods Part one: Primary HUVECs were isolated from fresh human umbilical veins and cultured, after immunomagnetic separation by anti-CD31 antibody coated Dynabeads, the HUVECs were indentified by FactorⅧimmuocytochemical staining and eletroscope observation; MTT method was carried out to assay the proliferation of HUVECs when treated with melatonin in concentrations from 0.1nmol/L to 1mmol/L (final concetration in the medium); and the cell cycle and apoptosis were detect using propidium iodione (PI) staining; the expressions of P53, Bax and Bcl-2 mRNA were detected by RT-PCR, also the proteins by immunofluorescence and Westem Blot anaysis. Part Two: the melatonin's receptors type expression in HUVECs was detected at first, and the interactions was observed when treated with melatonin; the possible intracellular signaling pathways include MAPK/ERK, PI3K/AKT and PKC were detected whether contributed to the anti-proliferative and pro-apoptotic effect of the indolamine in HUVECs by using specific inhibitors and activators; EMSA was used to detected the NF-κB binding activity in HUVECs when treated with melatonin and the relationship between NF-κB and its possible up-stream trigger signaling pathways.
Results Part one: (1) Primary HUVECs were isolated sucessfully from fresh human umbilical veins and cultured, afer purified by immunomagnetic separation. The endothelial origin was confirmed by the positive labeling of von Willebrand Factor (vWF), CD31 and electronmicropy observation. (2) At near physiological concentrations (1nmol/L), melatonin had no significant effect on cellular proliferation. However, melatonin in higher concentrations (greater than 10 nmol/L) significantly decreased cell proliferation, and the negative effect on HUVECs proliferation was enhanced with increasing melatonin concentrations. Melatonin of 1mmol/L had the greatest antiproliferative effect on HUVECs with the cell viability no difference between the control and the melatonin-treatment groups. (3) FCM showed HUVECs treated with melatonin in high concentrations presented a very distinct hypodiploid peak of apoptosis (0.64% vs 31.3%, P<0.01), and Cell cycle analyzed also showed a reduction of cells entering in the S phase (S phase arrest). (4) The Bax or P53 mRNA expression is increasing when treatment with 100nmol/L after 24hr, whereas no obvious changes to Bcl-2, but when incubated with 1mmol/L melatonin, a very early increasing expression of P53 and Bax mRNA at 3hr and a later decrease of Bcl-2 mRNA were shown. (4) The up-regulation of P53 and Bax and down-regulation of Bcl-2 proteins possibly contributed to the apoptotis in HUVECs with melatonin.
Part two: (1) In normal cultured HUVECs, G- protein- coupled membrane receptors of melatonin (MT1 and MT2) also with the nuclear receptors of melatonin (RORa and RORb, especially RORb) are both expressed, whereas no obvious expression of RORc in HUVECs. (2) The membrane receptors was involved in melatonin antiproliferative properties in HUVECs, and the receptor antagonist Luzindole could partially prevent the indolamine's efficacy. (3) In cultured HUVECs, melatonin, even at physiological concentrations, could suppress the expression of melatonin receptors, and it may be the outcome of a direct or indirect melatonin-mediated activation of constitutive PKCα. (4) The survival and proliferation of HUVECs is dependent on the activation of several intracellular signaling pathways include mitogen-activated protein kinases (MAPK)/extracellualar signal-related kinases (ERK), phosphoinositol-3-kinase (PI3K)/AKT and protein kinases C (PKC), and the blockade of these pathways by specifical inhibitors could decrease the cell growth rate respectively. (5) High concentration melatonin reduced the proliferation and induced the apoptosis direct or indirect by inactivation the ERK, PI3K/AKT and PKC, with the fact that the antiproliferative effect was partially regulated by its special inhibitors and activators. (6) HUVECs showed basal activation of NF-κB transcription factor, and high concetration melatonin inhibited the NF-κB expression and its binding to DNA. (7) All the signaling pathways specical inhibior could partially inhbit the NF-κB binding to DNA, thus suggest melatonin inhibited NF-κB activity possibly through inactivating these pathways, which may be responsible for the antiproliferative and pro-apoptotic effect of melatonin in HUVECs.
引文
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