白藜芦醇对外周血内皮祖细胞的影响及其机制研究
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摘要
内皮祖细胞(endothelial prcgenitor cells，EPCs)是一类能高度增殖、特异性的分化为血管内皮细胞、但尚未表达成熟血管内皮细胞表型的前体细胞。大量研究表明，成年个体体内的EPCs不仅参与血管形成(angiogenesis)，同时也参与出生后血管发生(vasculogenesis)和血管内膜损伤后修复。近来研究表明内皮功能不全在冠心病的发生、发展中扮演了重要角色。EPCs能通过修复内皮损伤，保持内膜完整性，从而抑制局部粥样硬化斑块和血栓的形成。然而诸如老龄、糖尿病、高血压、高胆固醇血症、高同型半胱氨酸血症及吸烟等冠心病危险因素对循环EPCs数量和活性具有明显抑制作用。
流行病学研究显示法国南部居民具有高胆固醇饮食习惯，然而其冠心病的发病率与死亡率却低于欧美其它地区，此即“法国悖论(French paradox)”。该现象被认为与该地区居民经常饮用红葡萄酒有关。白藜芦醇(resveratrol)是红葡萄酒中含量很高的一种非黄酮类多酚化合物，化学名为3，5，4’-三羟基二苯乙烯(3，5，4’-trihydroxy-stilbene)，分子式为C_(14)H_(12)O_3，分子量为228．2。天然的白藜芦醇存在于葡萄、花生、桑葚、虎杖等70多种植物中，是植物在应激犬态下(如紫外线照射、缺水、真菌感染等)产生的一种植物抗毒素。新近研究显示白藜芦醇对心血管系统具有多重效应，包括抑制动脉粥样硬化、保护心肌缺血再灌注损伤、逆转损伤血管新生内膜过度增生、调节血小板粘附与聚集、预防低密度脂蛋白氧化及升高密度脂蛋白等，被认为是介导红葡萄酒心血管保护作用的主要功能因子。然而，到目前为止，国内外关于白藜芦醇对EPCs数量和功能的直接影响的报道极少，特别是对其相关机制的研究未见报道。
综合国内外文献，我们提出假设：白藜芦醇可以通过影响EPCs的数量和功能，继而影响内皮修复能力，维持内皮损伤和修复之间的动态平衡，促进内皮功能的恢复，进而延缓动脉粥样硬化的发生、发展。为此，我们首先观察了白藜芦醇体外干预对外周血EPCs数量和功能的影响，随后进一步探讨了白藜芦醇影响EPCs数量和功能的可能机制。以下分两部分对本研究的方法、结果以及结论作一简述。
第一部分白藜芦醇对外周血内皮祖细胞数量和功能的影响
目的：观察resveratrol体外干预对外周血EPCs数量和功能的影响。
方法：采用密度梯度离心法从外周血获取单个核细胞，将其接种在人纤维连接蛋白包被的培养板，培养4d后，收集贴壁细胞，加入不同浓度resveratrol(10μmol/L，25μmol/L，50μmol/L和100μmol/L)干预，观察量效关系。多波长激光共聚焦显微镜鉴定FITC-UEA-Ⅰ和DiI-acLDL双染色阳性细胞为正在分化的EPCs，流式细胞仪检测其表面标志进一步鉴定EPCs。采用MTT比色法、改良的Boyden小室法、粘附实验、体外小管形成实验、ELISA实验分别观察EPCs的增殖能力、迁移能力、粘附能力、血管生成能力和分泌细胞因子能力。
结果：Resveratrol能显著增加外周血EPCs数量，并能明显增加EPCs的增殖、迁移、粘附、血管生成和分泌细胞因子能力，并且作用呈浓度依赖性，在50μmol/L组(与对照组比较，EPCs数量85．8±26．0 vs 44．8±9．6/hpf，P＜0．01；增殖能力0．296±0．028 vs 0．196±0．015，P＜0．01；迁移能力24．0±5．2 vs 10．7±3．2/hpf,P＜0．01；粘附能力49±6．3 vs 30±5．0/hpf,P＜0．01；血管生成能力49±6．3 vs 26±4．2/hpf，P＜0．01；分泌细胞因子能力377±28．8 vs 282±20．1pg/mL，P＜0．01)达最大增加效应。
结论：Resveratrol可增加EPCs数量并增强EPCs功能，且resveratrol对EPCs的影响呈一定的量效关系。
第二部分白藜芦醇影响内皮祖细胞的机制研究——抑制内皮祖细胞的衰老
目的：研究resveratrol对EPCs衰老的影响及其信号转导途径。
方法：采用密度梯度离心法从外周血获取单个核细胞，将其接种在人纤维连接蛋白包被的培养板，培养4d后，换用新鲜培养基，并加入不同浓度resveratrol(10μmol/L，25μmol/L，501μmol/L和100μmol/L)干预，或先分别予以PI3K抑制剂(LY294002)、eNOS抑制剂(N~G-mono-methyl-L-arginine，L-NAME)、无内在活性的雌激素受体拮抗剂(ICI182780，faslodex)预处理，然后再用50μmol/Lresveratrol干预。延长培养7d以诱导细胞衰老。采用SA-β-半乳糖苷酶染色试剂盒检测衰老细胞。采用5-bromo-2′-deoxyuridine(BrdU)掺入实验、改良的Boyden小室法和集落生成实验检测EPCs的增殖、迁移和集落形成能力。FITC-AnnexinV/PI流式细胞仪检测EPCs凋亡。RT-PCR检测EPCs hTERT mRNA水平。端粒重复序列扩增法(telomeric repeat amplification protocol，TRAP)-聚丙烯酞胺凝胶电泳-银染法定性检测端粒酶活性，TRAP-ELISA定量检测端粒酶活性。Western blot实验检测EPCs Akt磷酸化水平。
结果：Resveratrol干预能减少SA-β-半乳糖苷酶阳性细胞数量，增加EPCs的增殖、迁移及集落形成能力，并且resveratrol的作用为浓度依赖性，在50μmol/L组达最大效应。Resveratrol对细胞衰老的作用可被LY294002阻断，但不能被L-NAME或ICI182780阻断。Resveratrol可以促进EPCs hTERT mRNA的表达，增加EPCs端粒酶活性。PI3K抑制剂可以抑制resveratrol对EPCs hTERT mRNA表达及端粒酶活性的促进作用。Western blot检测发现resveratrol可以促进Akt磷酸化。此外，50μmol/L resveratrol并不能明显减少EPCs凋亡。
结论：Resveratrol延缓EPCs衰老，伴随EPCs增殖、迁移及集落形成能力的增加；resveratrol延缓EPCs衰老可能跟EPCs端粒酶活性增加及hTERT mRNA的表达上调有关；PI3K/Akt信号转导途径可能参与resveratrol延缓EPCs衰老的调控。
Endothelial progenitor cells (EPCs) are a cell population which could circulate,proliferate,and differentiate into mature endothelial cells,but do not acquire matureendothelial lineage markers or form a lumen yet.EPCs have the capacity to incorporateinto the sites of physiological and pathological neovascularization in vivo.Recently,circulating EPCs have been identified as a marker of endothelial function andcardiovascular risk.Endothelial dysfunction is usually one of the earlier markers ofatherosclerosis,and predisposes to increased vascular tension and thrombosis.EPCsmay play an important role as an endogenous repair mechanism to maintain the integrityof the endothelial monolayer by replacing denuded parts of the vessel.The maintenanceof endothelial monolayer could inhibit thrombotic complication and atheroscleroticlesion development.The beneficial potential of EPCs is attractive for cell therapy whichtargets the endothelial regeneration.However,various risk factors for coronary arterydisease(CAD),such as aging,diabetes,hypertension,hypercholesterolemia,hyperhomocystenemia and smoking,attenuate the number and functional activity of EPCs in healthy individuals and CAD patients.Thus,in most cases,in vitro expansionof EPCs appears to be necessary for the autologous EPCs-based cell therapy.
Epidemiological studies have indicated that there is a low prevalence of ischaemicheart disease in the population of southern France,despite a diet rich in saturated fat andcholesterol.This so-called“French paradox”has been attributed to moderateconsumption of red wine.Resveratrol (3,5,4'-trihydroxystilbene),a polyphenolcompound found in significant amounts in grapes and red wine,has been designated theactive agent.However,the mechanisms of action of resveratrol are,as yet,unclear.Anemerging area of investigation has demonstrated critical and multiple actions ofresveratrol on CAD,such as inhibition of the early progression of atherosclerotic lesions,protection of cardiomyocytes against ischaemia-reperfusion injury and reversal ofneointimal formation of injured arteries.Moreover,a number of recent studies hasdemonstrated that resveratrol functioned to inhibit platelet aggregation and/or adhesion,lower oxidative stress in platelets,prevent low-density lipoprotein oxidation,suppressproliferation or hypertrophy of smooth muscle cells and increase high-densitylipoprotein.As far as we know,little study has been performed to investigate the directmodulatory effects of resveratrol on the number and function of EPCs,moreover,norelevant mechanism has been mentioned regarding these effects..
On the basis of these considerations,we hypothesized that resveratrol affectedEPCs number and function,thus influenced endothelial repair process and maintainedthe balance between the magnitude of injury and the capacity for repair,whichprevented thrombotic compiication and atherosclerotic lesion development.To test thishypothesis,we measured the number and functional activity of EPCs exposed toresveratrol in vitro at first.Then,we studied the mechanisms by which resveratrol actedon EPCs.
The aim of this study is to investigate the effects of resveratrol on number andfunctional activity of EPCs from peripheral blood.Total mononuclear cells (MNCs)were isolated from peripheral blood by Ficoll density gradient centrifugation,and thenthe cells were plated on fibronectin-coated culture dishes.After 4 days cultured,attached cells were stimulated with resveratrol (to make a series of final concentrations:10μmol/L,25μmol/L,50μmol/L,100μmol/L) or vehicle control.EPCs werecharacterized as adherent cells double positive for DiLDL-uptake and lectin binding bydirect fluorescent staining under a laser scanning confocal microscope.EPCs werefurther documented by demonstrating the expression of CD34,CD45,VE-cadherin,VEGFR-2 and AC133 with flow cytometry.EPCs proliferation,migration,in vitrovasculogenesis and secretion were assessed with MTT assay,modified Boyden chamberassay,in vitro tubule forming assay and ELISA assay respectively.EPCs adhesionassay was performed by replating those on fibronectin-coated dishes,and then adherentcells were counted.We showed that incubation of isolated human MNCs withresveratrol dose dependently increased the number of EPCs with the maximum at50μmol/L (to compare with that of control,85.8±26.0 vs 44.8±9.6/hpf,P＜0.01).Resveratrol significantly increased the proliferative,migratory,adhesive andvasculogenic capacities of EPCs,maximum at 50μmol/L (to compare with that ofcontrol,proliferative capacities 0.296±0.028 vs 0.196±0.015;migratory capacities 24.0±5.2 vs 10.7±3.2/hpf;adhesive capacities 49±6.3 vs 30±5.0/hpf;vasculogeniccapacities 49±6.3 vs 26±4.2/hpf,;secretion capacity 377±28.8 vs 282±20.1pg/mL;P＜0.01 for each comparision).
Part 2:Resveratrol reduces senescence of endothelial progenitorcells through telomerase activation
Emerging evidence has suggested that reduced EPCs number and activity wasassociated with EPC senescence which involved with telomerase activity.Resveratrolhas been shown to augment a variety of cellular functions of EPCs and subsequentlycontribute to ischemic neovascularization.Therefore,we investigated whetherresveratrol might be able to prevent senescence of EPCs through telomerase activation.EPCs were isolated from peripheral blood and characterized.After ex-vivo prolongedcultivation,EPCs became senescence as determined by acidicβ-galactosidase staining.Resveratrol dose-dependently inhibited the onset of EPC senescence in culture,maximum at 50μmol/L.The effect of resveratrol on senescence was significantlyattenuated by the highly selective phosphoinositide 3-kinase (PI3K) inhibitor(LY294002),but not by the eNOS inhibitor N~G -mono-methyl-L-arginine (L-NAME) orthe estrogen receptor (ER) blocker faslodex (ICI182780).Resveratrol increasedtelomerase activity dose-dependently,which was accompanied with up-regulation of thecatalytic subunit,telomerase reverse transcriptase (TERT),and these effects were alsosignificantly attenuated by LY294002.Immunoblotting analysis showed that treatmentof EPCs with resveratrol resulted in time and dose-dependent Akt phosphorylation.Inaddition,resveratrol.increased proliferative as well as migratory activity of EPCs asassessed by 5-bromo-2'-deoxyuridine (BrdU) incorporation assay,colony-forming assayand modified boyden chamber assay.But 50μmol/L resveratrol failed to reduce EPCs apoptosis significantly.In conclusions,resveratrol delays the onset of EPC senescence,which may be related to telomerase activation by the Akt-dependent mechanism
流行病学研究显示法国南部居民具有高胆固醇饮食习惯，然而其冠心病的发病率与死亡率却低于欧美其它地区，此即“法国悖论(French paradox)”。该现象被认为与该地区居民经常饮用红葡萄酒有关。白藜芦醇(resveratrol)是红葡萄酒中含量很高的一种非黄酮类多酚化合物，化学名为3，5，4’-三羟基二苯乙烯(3，5，4’-trihydroxy-stilbene)，分子式为C_(14)H_(12)O_3，分子量为228．2。天然的白藜芦醇存在于葡萄、花生、桑葚、虎杖等70多种植物中，是植物在应激犬态下(如紫外线照射、缺水、真菌感染等)产生的一种植物抗毒素。新近研究显示白藜芦醇对心血管系统具有多重效应，包括抑制动脉粥样硬化、保护心肌缺血再灌注损伤、逆转损伤血管新生内膜过度增生、调节血小板粘附与聚集、预防低密度脂蛋白氧化及升高密度脂蛋白等，被认为是介导红葡萄酒心血管保护作用的主要功能因子。然而，到目前为止，国内外关于白藜芦醇对EPCs数量和功能的直接影响的报道极少，特别是对其相关机制的研究未见报道。
综合国内外文献，我们提出假设：白藜芦醇可以通过影响EPCs的数量和功能，继而影响内皮修复能力，维持内皮损伤和修复之间的动态平衡，促进内皮功能的恢复，进而延缓动脉粥样硬化的发生、发展。为此，我们首先观察了白藜芦醇体外干预对外周血EPCs数量和功能的影响，随后进一步探讨了白藜芦醇影响EPCs数量和功能的可能机制。以下分两部分对本研究的方法、结果以及结论作一简述。
第一部分白藜芦醇对外周血内皮祖细胞数量和功能的影响
目的：观察resveratrol体外干预对外周血EPCs数量和功能的影响。
方法：采用密度梯度离心法从外周血获取单个核细胞，将其接种在人纤维连接蛋白包被的培养板，培养4d后，收集贴壁细胞，加入不同浓度resveratrol(10μmol/L，25μmol/L，50μmol/L和100μmol/L)干预，观察量效关系。多波长激光共聚焦显微镜鉴定FITC-UEA-Ⅰ和DiI-acLDL双染色阳性细胞为正在分化的EPCs，流式细胞仪检测其表面标志进一步鉴定EPCs。采用MTT比色法、改良的Boyden小室法、粘附实验、体外小管形成实验、ELISA实验分别观察EPCs的增殖能力、迁移能力、粘附能力、血管生成能力和分泌细胞因子能力。
结果：Resveratrol能显著增加外周血EPCs数量，并能明显增加EPCs的增殖、迁移、粘附、血管生成和分泌细胞因子能力，并且作用呈浓度依赖性，在50μmol/L组(与对照组比较，EPCs数量85．8±26．0 vs 44．8±9．6/hpf，P＜0．01；增殖能力0．296±0．028 vs 0．196±0．015，P＜0．01；迁移能力24．0±5．2 vs 10．7±3．2/hpf,P＜0．01；粘附能力49±6．3 vs 30±5．0/hpf,P＜0．01；血管生成能力49±6．3 vs 26±4．2/hpf，P＜0．01；分泌细胞因子能力377±28．8 vs 282±20．1pg/mL，P＜0．01)达最大增加效应。
结论：Resveratrol可增加EPCs数量并增强EPCs功能，且resveratrol对EPCs的影响呈一定的量效关系。
第二部分白藜芦醇影响内皮祖细胞的机制研究——抑制内皮祖细胞的衰老
目的：研究resveratrol对EPCs衰老的影响及其信号转导途径。
方法：采用密度梯度离心法从外周血获取单个核细胞，将其接种在人纤维连接蛋白包被的培养板，培养4d后，换用新鲜培养基，并加入不同浓度resveratrol(10μmol/L，25μmol/L，501μmol/L和100μmol/L)干预，或先分别予以PI3K抑制剂(LY294002)、eNOS抑制剂(N~G-mono-methyl-L-arginine，L-NAME)、无内在活性的雌激素受体拮抗剂(ICI182780，faslodex)预处理，然后再用50μmol/Lresveratrol干预。延长培养7d以诱导细胞衰老。采用SA-β-半乳糖苷酶染色试剂盒检测衰老细胞。采用5-bromo-2′-deoxyuridine(BrdU)掺入实验、改良的Boyden小室法和集落生成实验检测EPCs的增殖、迁移和集落形成能力。FITC-AnnexinV/PI流式细胞仪检测EPCs凋亡。RT-PCR检测EPCs hTERT mRNA水平。端粒重复序列扩增法(telomeric repeat amplification protocol，TRAP)-聚丙烯酞胺凝胶电泳-银染法定性检测端粒酶活性，TRAP-ELISA定量检测端粒酶活性。Western blot实验检测EPCs Akt磷酸化水平。
结果：Resveratrol干预能减少SA-β-半乳糖苷酶阳性细胞数量，增加EPCs的增殖、迁移及集落形成能力，并且resveratrol的作用为浓度依赖性，在50μmol/L组达最大效应。Resveratrol对细胞衰老的作用可被LY294002阻断，但不能被L-NAME或ICI182780阻断。Resveratrol可以促进EPCs hTERT mRNA的表达，增加EPCs端粒酶活性。PI3K抑制剂可以抑制resveratrol对EPCs hTERT mRNA表达及端粒酶活性的促进作用。Western blot检测发现resveratrol可以促进Akt磷酸化。此外，50μmol/L resveratrol并不能明显减少EPCs凋亡。
结论：Resveratrol延缓EPCs衰老，伴随EPCs增殖、迁移及集落形成能力的增加；resveratrol延缓EPCs衰老可能跟EPCs端粒酶活性增加及hTERT mRNA的表达上调有关；PI3K/Akt信号转导途径可能参与resveratrol延缓EPCs衰老的调控。
Endothelial progenitor cells (EPCs) are a cell population which could circulate,proliferate,and differentiate into mature endothelial cells,but do not acquire matureendothelial lineage markers or form a lumen yet.EPCs have the capacity to incorporateinto the sites of physiological and pathological neovascularization in vivo.Recently,circulating EPCs have been identified as a marker of endothelial function andcardiovascular risk.Endothelial dysfunction is usually one of the earlier markers ofatherosclerosis,and predisposes to increased vascular tension and thrombosis.EPCsmay play an important role as an endogenous repair mechanism to maintain the integrityof the endothelial monolayer by replacing denuded parts of the vessel.The maintenanceof endothelial monolayer could inhibit thrombotic complication and atheroscleroticlesion development.The beneficial potential of EPCs is attractive for cell therapy whichtargets the endothelial regeneration.However,various risk factors for coronary arterydisease(CAD),such as aging,diabetes,hypertension,hypercholesterolemia,hyperhomocystenemia and smoking,attenuate the number and functional activity of EPCs in healthy individuals and CAD patients.Thus,in most cases,in vitro expansionof EPCs appears to be necessary for the autologous EPCs-based cell therapy.
Epidemiological studies have indicated that there is a low prevalence of ischaemicheart disease in the population of southern France,despite a diet rich in saturated fat andcholesterol.This so-called“French paradox”has been attributed to moderateconsumption of red wine.Resveratrol (3,5,4'-trihydroxystilbene),a polyphenolcompound found in significant amounts in grapes and red wine,has been designated theactive agent.However,the mechanisms of action of resveratrol are,as yet,unclear.Anemerging area of investigation has demonstrated critical and multiple actions ofresveratrol on CAD,such as inhibition of the early progression of atherosclerotic lesions,protection of cardiomyocytes against ischaemia-reperfusion injury and reversal ofneointimal formation of injured arteries.Moreover,a number of recent studies hasdemonstrated that resveratrol functioned to inhibit platelet aggregation and/or adhesion,lower oxidative stress in platelets,prevent low-density lipoprotein oxidation,suppressproliferation or hypertrophy of smooth muscle cells and increase high-densitylipoprotein.As far as we know,little study has been performed to investigate the directmodulatory effects of resveratrol on the number and function of EPCs,moreover,norelevant mechanism has been mentioned regarding these effects..
On the basis of these considerations,we hypothesized that resveratrol affectedEPCs number and function,thus influenced endothelial repair process and maintainedthe balance between the magnitude of injury and the capacity for repair,whichprevented thrombotic compiication and atherosclerotic lesion development.To test thishypothesis,we measured the number and functional activity of EPCs exposed toresveratrol in vitro at first.Then,we studied the mechanisms by which resveratrol actedon EPCs.
The aim of this study is to investigate the effects of resveratrol on number andfunctional activity of EPCs from peripheral blood.Total mononuclear cells (MNCs)were isolated from peripheral blood by Ficoll density gradient centrifugation,and thenthe cells were plated on fibronectin-coated culture dishes.After 4 days cultured,attached cells were stimulated with resveratrol (to make a series of final concentrations:10μmol/L,25μmol/L,50μmol/L,100μmol/L) or vehicle control.EPCs werecharacterized as adherent cells double positive for DiLDL-uptake and lectin binding bydirect fluorescent staining under a laser scanning confocal microscope.EPCs werefurther documented by demonstrating the expression of CD34,CD45,VE-cadherin,VEGFR-2 and AC133 with flow cytometry.EPCs proliferation,migration,in vitrovasculogenesis and secretion were assessed with MTT assay,modified Boyden chamberassay,in vitro tubule forming assay and ELISA assay respectively.EPCs adhesionassay was performed by replating those on fibronectin-coated dishes,and then adherentcells were counted.We showed that incubation of isolated human MNCs withresveratrol dose dependently increased the number of EPCs with the maximum at50μmol/L (to compare with that of control,85.8±26.0 vs 44.8±9.6/hpf,P＜0.01).Resveratrol significantly increased the proliferative,migratory,adhesive andvasculogenic capacities of EPCs,maximum at 50μmol/L (to compare with that ofcontrol,proliferative capacities 0.296±0.028 vs 0.196±0.015;migratory capacities 24.0±5.2 vs 10.7±3.2/hpf;adhesive capacities 49±6.3 vs 30±5.0/hpf;vasculogeniccapacities 49±6.3 vs 26±4.2/hpf,;secretion capacity 377±28.8 vs 282±20.1pg/mL;P＜0.01 for each comparision).
Part 2:Resveratrol reduces senescence of endothelial progenitorcells through telomerase activation
Emerging evidence has suggested that reduced EPCs number and activity wasassociated with EPC senescence which involved with telomerase activity.Resveratrolhas been shown to augment a variety of cellular functions of EPCs and subsequentlycontribute to ischemic neovascularization.Therefore,we investigated whetherresveratrol might be able to prevent senescence of EPCs through telomerase activation.EPCs were isolated from peripheral blood and characterized.After ex-vivo prolongedcultivation,EPCs became senescence as determined by acidicβ-galactosidase staining.Resveratrol dose-dependently inhibited the onset of EPC senescence in culture,maximum at 50μmol/L.The effect of resveratrol on senescence was significantlyattenuated by the highly selective phosphoinositide 3-kinase (PI3K) inhibitor(LY294002),but not by the eNOS inhibitor N~G -mono-methyl-L-arginine (L-NAME) orthe estrogen receptor (ER) blocker faslodex (ICI182780).Resveratrol increasedtelomerase activity dose-dependently,which was accompanied with up-regulation of thecatalytic subunit,telomerase reverse transcriptase (TERT),and these effects were alsosignificantly attenuated by LY294002.Immunoblotting analysis showed that treatmentof EPCs with resveratrol resulted in time and dose-dependent Akt phosphorylation.Inaddition,resveratrol.increased proliferative as well as migratory activity of EPCs asassessed by 5-bromo-2'-deoxyuridine (BrdU) incorporation assay,colony-forming assayand modified boyden chamber assay.But 50μmol/L resveratrol failed to reduce EPCs apoptosis significantly.In conclusions,resveratrol delays the onset of EPC senescence,which may be related to telomerase activation by the Akt-dependent mechanism
引文
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