内皮氧化损伤体外分析系统的建立及在药效评价中的应用
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摘要
内皮细胞是覆盖在血管腔内表面的单层细胞，可以通过分泌多种活性物质参与心血管系统功能的调节。许多心血管疾病及危险因素均可以导致内皮功能损伤，而内皮功能损伤又常伴发和加重心血管疾病。引起内皮细胞损伤的原因很多，氧化应激引起的内皮细胞氧化损伤是引起内皮功能障碍的一个重要原因。本课题利用细胞阻抗微阵列传感器及计算机图像处理等工程手段在体外建立了单核细胞-内皮静态粘附及动态粘附定量分析模型，同时结合流式细胞术、激光共聚焦显微技术、免疫细胞化学、活体细胞染色等多种传统生化技术手段，较为系统和全面的建立了体外内皮氧化损伤分析系统，并将此系统应用于药效评价中，对金丝桃苷药效做以研究。为心血管疾病相关药物筛选提供了一个高效、定量、敏感的平台，也为筛选出的药物的开发提供理论依据。
本研究在体外建立了利用基于细胞阻抗分析白细胞-内皮细胞静态粘附分析模型。利用RT-CES系统，观察研究白细胞粘附过程中内皮细胞与胞外基质间粘附性的变化，并通过与传统生化方法的比较，验证了此方法的可行性和准确性。
在体外建立了单核细胞-内皮细胞动态粘附模型。利用流动小室系统和荧光标记技术，在体外模拟血流动力学条件，结合图像处理技术，定量分析了单核细胞运动速度等参数。
通过内皮细胞代谢活性、凋亡坏死、线粒体功能及凋亡相关蛋白表达几个方面，建立了体外氧化损伤致内皮凋亡的定量分析模型。在此模型上，研究了金丝桃苷对氧化损伤所致内皮细胞凋亡坏死的作用及可能的作用途径。结果表明金丝桃苷可以抑制氧化损伤造成的内皮细胞的凋亡和坏死、线粒体功能紊乱及Bax表达增高，并可以增强Bcl-2的表达，证明抑制细胞凋亡坏死是金丝桃苷的内皮保护作用的重要机制，而Bax和Bcl-2则是金丝桃苷抑制内皮细胞凋亡的重要途径之一。
利用基于细胞阻抗分析的单核细胞-内皮细胞静态粘附体外分析模型，研究了金丝桃苷对氧化损伤后内皮细胞表面粘附分子ICAM-1和E-Selectin表达的作用及对单核细胞粘附个数、内皮细胞阻抗变化的影响。利用单核细胞-内皮细胞动态粘附模型体外定量分析系统，研究了剪切力条件下，金丝桃苷对氧化损伤引起的单核细胞-内皮细胞粘附的影响。发现金丝桃苷可以降低两种粘附分子的表达，减少单核细胞静态粘附个数及增高粘附过程中内皮细胞细胞指数(cellindex，CI)值，同时金丝桃苷还可以提高动态粘附条件下单核细胞的慢速滚动速度，减少慢速滚动和牢固粘附的单核细胞的数目。提示金丝桃苷下调内皮细胞表面粘附分子，从而减少单核细胞静／动态粘附个数，增加内皮细胞与胞外基质的粘附性、加快单核细胞滚动速度是金丝桃苷发挥其内皮保护作用另一重要机制。
综上，本课题的主要创新之处在于：1.利用RT-CES系统，建立了基于细胞阻抗分析的单核细胞-内皮细胞静态粘附体外分析模型，研究单核细胞粘附过程中内皮细胞与胞外基质间粘附性变化，较之传统的生化分析手段，具有免标记、实时动态、操作简便等优点。2.利用流动小室系统及图像处理技术，建立了单核细胞-内皮细胞动态粘附模型，并定量分析了单核细胞运动速度等运动参数。3.利用上述模型并结合传统生化分析手段，在体外建立了内皮氧化损伤定量分析系统，并将此系统应用于金丝桃苷的药效评价。研究结果表明金丝桃苷具有一定的内皮保护作用，该作用可能是通过抑制Bax表达和增强Bcl-2的表达，同时在抑制细胞线粒体膜电势损失、降低胞内自由基含量和增强细胞抗氧化性损伤等作用的共同参与下，抑制动脉粥样硬化发生过程中内皮细胞的凋亡和继发性的坏死；通过抑制损伤处内皮细胞表面粘附分子的表达及增加内皮细胞与胞外基质的粘附性，减少单核细胞向内膜下的迁移，继而减少巨噬细胞源泡沫细胞的形成。
Vascular endothelial cells form a single cell layer that lines allblood vessels and participate in cardiovascular function regulation.Endothelial dysfunction is involved in many cardiovascular diseases.Many studies indicated that oxidative stress plays an important role inendothelial dysfunction. In the present study, we employed diversebiomedical techniques such as cell-based impedance sensing,quantitative image processing, flow cytometry, confocal imaging,immuocytochemistry and live cell labeling to establish a quantitativeanalysis system to investigate endothelial dysfunction induced byoxidative damage. Furthermore, this quantitative system was applied toevaluate the effects of Hyperoside. This system would be helpful to drugdiscovery and biomedical mechanisms investigation.
We applied a non-invasive biosensor system referred to as real-timecell electronic sensor (RT-CES) system to monitor the changes inendothelial cell-substrate adhesion induced by monocyte adhesion in adynamic and quantitative manner, while the number of adherent U937 cellsto the endothelial cells was verified bya standard assay. Furthermore,decrease in FAK protein level and F-actin rearrangement in endothelialcells were observed after addition of U937 cells. Our results indicatethat the adhesion of U937 cells to LPS-treated endothelial ceils reducesthe cell adhesiveness to the substrate, and such reduction may facilitateinfiltration of leukocytes.
Based on the culture of endothelial ceils and cellularmicrofluorescence image processing technique, a new method was developedto study the adhesion between endothelial ceils and leukocytes undershear stress by simulating the blood flow in vitro. Employing inversemicrofluorescence imaging and image processing technique, theinteraction between monocytes and endothelial cells under flow condition, was studied quantificationally and objectively.
The effect of hyperoside on cndothelial cell damage was studied onendothelial cell oxidative damage model induced by H_2O_2 of cultured humanumbilical vein endothelial cells (HUVEC). The results showed thathyperoside could reduce apoptosis, necrosis, the loss of mitochondrialmembrane potential and the ROS content of endothelial cells induced byH_2O_2, decrease the expression of Bax and increase the expression of Bcl-2.These results proved that reduction of apoptosis and necrosis may be oneof important mechanisms of protective effects of hyperoside onehdothelial cells, and inhibiton of Bax expression and increasing Bcl-2expression were important mechanisms of anti-apoptosis effect ofhyperoside on endothelial cells.
On endothelial cells damage model induced by oxLDL in vitro, the effectof hyperoside on ICAM-1 and E-Selectin expression andmonocytes-endothelial cell adhesion were investigated. The resultsshowed that hyperoside could decrease the number of adherent monocytes,increase the CI value during monocytes-endothelial cell binding, anddecrease the velocity and number of slow roiling monocytes by decreasingthe expression of ICAM-1 and E-Selectin. Therefore hyperoside may reducethe adherence of monocytes on oxLDL treated-HUVECs. It may be anotherimportant mechanism of protective effect of hyperoside on endothelialcells.
In conclusion, our study achieved the following novel findings: 1. Withthe application of RT-CES system, study on endothelial cell-substrateadhesiveness during leukocyte binding was carried out in a label-free,dynamic, convenient and quantitative way. 2. With the application of flowchamber system and image processing technique, the monocytes wererecognized and counted, and themonocytes' rollingvelocity was measured.3. Two above mentioned methods and traditional biochemical methods were employed in this study to estabilish a quantitative system to analyzeendothelial dysfunction induced by oxidative damage. Additionally, theprotective effects of hyperoside on endothelial cells were investigated.The results showed that hyperoside protected endothelial cells againstoxidative damage by inhibiting apoptosis, necorsis and mitochondrialdysfunction, reducing ROS content and Bax expression, increasing Bcl-2expression, and reduced the interaction between monocytes andendothelial cells.
本研究在体外建立了利用基于细胞阻抗分析白细胞-内皮细胞静态粘附分析模型。利用RT-CES系统，观察研究白细胞粘附过程中内皮细胞与胞外基质间粘附性的变化，并通过与传统生化方法的比较，验证了此方法的可行性和准确性。
在体外建立了单核细胞-内皮细胞动态粘附模型。利用流动小室系统和荧光标记技术，在体外模拟血流动力学条件，结合图像处理技术，定量分析了单核细胞运动速度等参数。
通过内皮细胞代谢活性、凋亡坏死、线粒体功能及凋亡相关蛋白表达几个方面，建立了体外氧化损伤致内皮凋亡的定量分析模型。在此模型上，研究了金丝桃苷对氧化损伤所致内皮细胞凋亡坏死的作用及可能的作用途径。结果表明金丝桃苷可以抑制氧化损伤造成的内皮细胞的凋亡和坏死、线粒体功能紊乱及Bax表达增高，并可以增强Bcl-2的表达，证明抑制细胞凋亡坏死是金丝桃苷的内皮保护作用的重要机制，而Bax和Bcl-2则是金丝桃苷抑制内皮细胞凋亡的重要途径之一。
利用基于细胞阻抗分析的单核细胞-内皮细胞静态粘附体外分析模型，研究了金丝桃苷对氧化损伤后内皮细胞表面粘附分子ICAM-1和E-Selectin表达的作用及对单核细胞粘附个数、内皮细胞阻抗变化的影响。利用单核细胞-内皮细胞动态粘附模型体外定量分析系统，研究了剪切力条件下，金丝桃苷对氧化损伤引起的单核细胞-内皮细胞粘附的影响。发现金丝桃苷可以降低两种粘附分子的表达，减少单核细胞静态粘附个数及增高粘附过程中内皮细胞细胞指数(cellindex，CI)值，同时金丝桃苷还可以提高动态粘附条件下单核细胞的慢速滚动速度，减少慢速滚动和牢固粘附的单核细胞的数目。提示金丝桃苷下调内皮细胞表面粘附分子，从而减少单核细胞静／动态粘附个数，增加内皮细胞与胞外基质的粘附性、加快单核细胞滚动速度是金丝桃苷发挥其内皮保护作用另一重要机制。
综上，本课题的主要创新之处在于：1.利用RT-CES系统，建立了基于细胞阻抗分析的单核细胞-内皮细胞静态粘附体外分析模型，研究单核细胞粘附过程中内皮细胞与胞外基质间粘附性变化，较之传统的生化分析手段，具有免标记、实时动态、操作简便等优点。2.利用流动小室系统及图像处理技术，建立了单核细胞-内皮细胞动态粘附模型，并定量分析了单核细胞运动速度等运动参数。3.利用上述模型并结合传统生化分析手段，在体外建立了内皮氧化损伤定量分析系统，并将此系统应用于金丝桃苷的药效评价。研究结果表明金丝桃苷具有一定的内皮保护作用，该作用可能是通过抑制Bax表达和增强Bcl-2的表达，同时在抑制细胞线粒体膜电势损失、降低胞内自由基含量和增强细胞抗氧化性损伤等作用的共同参与下，抑制动脉粥样硬化发生过程中内皮细胞的凋亡和继发性的坏死；通过抑制损伤处内皮细胞表面粘附分子的表达及增加内皮细胞与胞外基质的粘附性，减少单核细胞向内膜下的迁移，继而减少巨噬细胞源泡沫细胞的形成。
Vascular endothelial cells form a single cell layer that lines allblood vessels and participate in cardiovascular function regulation.Endothelial dysfunction is involved in many cardiovascular diseases.Many studies indicated that oxidative stress plays an important role inendothelial dysfunction. In the present study, we employed diversebiomedical techniques such as cell-based impedance sensing,quantitative image processing, flow cytometry, confocal imaging,immuocytochemistry and live cell labeling to establish a quantitativeanalysis system to investigate endothelial dysfunction induced byoxidative damage. Furthermore, this quantitative system was applied toevaluate the effects of Hyperoside. This system would be helpful to drugdiscovery and biomedical mechanisms investigation.
We applied a non-invasive biosensor system referred to as real-timecell electronic sensor (RT-CES) system to monitor the changes inendothelial cell-substrate adhesion induced by monocyte adhesion in adynamic and quantitative manner, while the number of adherent U937 cellsto the endothelial cells was verified bya standard assay. Furthermore,decrease in FAK protein level and F-actin rearrangement in endothelialcells were observed after addition of U937 cells. Our results indicatethat the adhesion of U937 cells to LPS-treated endothelial ceils reducesthe cell adhesiveness to the substrate, and such reduction may facilitateinfiltration of leukocytes.
Based on the culture of endothelial ceils and cellularmicrofluorescence image processing technique, a new method was developedto study the adhesion between endothelial ceils and leukocytes undershear stress by simulating the blood flow in vitro. Employing inversemicrofluorescence imaging and image processing technique, theinteraction between monocytes and endothelial cells under flow condition, was studied quantificationally and objectively.
The effect of hyperoside on cndothelial cell damage was studied onendothelial cell oxidative damage model induced by H_2O_2 of cultured humanumbilical vein endothelial cells (HUVEC). The results showed thathyperoside could reduce apoptosis, necrosis, the loss of mitochondrialmembrane potential and the ROS content of endothelial cells induced byH_2O_2, decrease the expression of Bax and increase the expression of Bcl-2.These results proved that reduction of apoptosis and necrosis may be oneof important mechanisms of protective effects of hyperoside onehdothelial cells, and inhibiton of Bax expression and increasing Bcl-2expression were important mechanisms of anti-apoptosis effect ofhyperoside on endothelial cells.
On endothelial cells damage model induced by oxLDL in vitro, the effectof hyperoside on ICAM-1 and E-Selectin expression andmonocytes-endothelial cell adhesion were investigated. The resultsshowed that hyperoside could decrease the number of adherent monocytes,increase the CI value during monocytes-endothelial cell binding, anddecrease the velocity and number of slow roiling monocytes by decreasingthe expression of ICAM-1 and E-Selectin. Therefore hyperoside may reducethe adherence of monocytes on oxLDL treated-HUVECs. It may be anotherimportant mechanism of protective effect of hyperoside on endothelialcells.
In conclusion, our study achieved the following novel findings: 1. Withthe application of RT-CES system, study on endothelial cell-substrateadhesiveness during leukocyte binding was carried out in a label-free,dynamic, convenient and quantitative way. 2. With the application of flowchamber system and image processing technique, the monocytes wererecognized and counted, and themonocytes' rollingvelocity was measured.3. Two above mentioned methods and traditional biochemical methods were employed in this study to estabilish a quantitative system to analyzeendothelial dysfunction induced by oxidative damage. Additionally, theprotective effects of hyperoside on endothelial cells were investigated.The results showed that hyperoside protected endothelial cells againstoxidative damage by inhibiting apoptosis, necorsis and mitochondrialdysfunction, reducing ROS content and Bax expression, increasing Bcl-2expression, and reduced the interaction between monocytes andendothelial cells.
引文
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