脂氧素A_4调节人脐静脉内皮细胞通透性的机制初探
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摘要
研究背景:血管内皮作为机体调节心脑血管系统稳态最大的代谢和内分泌器官越来越受到重视,其重要功能之一即是作为血液和组织间物质转运的屏障,一旦血管内皮细胞受损,则必将影响甚至破坏内皮细胞正常的生物学功能,最明显的表现即是血管内皮的通透性增加,它将导致全身系统性的疾病产生,诸如动脉粥样硬化形成,高血压,先兆子痫引起的水肿等疾病。因此,如何保护内皮细胞免受损害,维持正常的内皮通透性显然成为了心脑血管等疾病预防领域的研究热点。由于炎性氧化应激引起内皮细胞通透性增加引起血栓、水肿是心血管疾病、微血管功能障碍的重要致病表现。而脂氧素(Lipoxins,LXs)作为第一个在活体内被鉴定的内源性刹车信号家族成员,具有促进炎症消退的作用,于此同时本实验室组曾报道脂氧素在脂多糖刺激的巨噬细胞中能够发挥抗氧化作用,病理性妊娠及心血管疾病患者的血中脂氧素含量相当低,这提示我们脂氧素很有可能对炎性氧化应激引起内皮细胞通透性增加起到缓解作用以维持正常的内皮功能。
目的:探讨脂氧素对脂多糖诱导人脐静脉内皮细胞高通透性的调节及其作用机制。
方法:培养人脐静脉内皮细胞株CRL-1730,实验分为三组:空白对照组,脂多糖(Lipopolysaccharide,LPS)刺激组,脂多糖(LPS)+脂氧素A_4(LXA_4)干预组,苏木精-伊红染色法(Hematoxylin&Eosine,HE)观察细胞的形态变化,单层内皮细胞通透性测定方法测定细胞通透性,活性氧试剂盒检测活性氧(Reactive Oxygen Species,ROS)含量,Real-time PCR检测(Formyl-peptide receptor like 2, FPRL2)受体的表达,RT-PCR法分别检测血管内皮钙粘附素(VE-cadherin)、β-catenin、瞬间受体电位通道(Transient receptor potential channel 1,TRPC1)的mRNA水平,免疫印迹法检测VE-cadherin、β-catenin的蛋白含量,荧光免疫细胞化学法观察VE-cadherin的表达,钙成像技术检测细胞内钙浓度的变化。
结果:⑴. LXA_4刺激后,CRL-1730的FPRL2受体表达与原代HUVEC细胞受体表达量接近且LXA_4能够上调FPRL2的表达。
⑵与对照组相比,LPS刺激组细胞形态变圆且小,细胞与细胞之间间隙变大,LPS+LXA_4组接近正常对照组。
⑶与对照组相比,LPS刺激组细胞的通透性明显增加(**P<0.01).,LPS+LXA_4组能有效的抑制通透性的变化(**P<0.01),但无LXA_4剂量依赖性,LPS+LXA_4+BOC-2组通透性仍然增加(**P<0.05),进一步验证人脐静脉内皮细胞株发挥作用很可能由脂氧素受体FPRL2介导。
⑷与对照组相比,LPS刺激组VE-cadherin、β-catenin的mRNA及蛋白水平均下调,TRPC1的mRNA水平增加(*P<0.05),免疫荧光显示VE-cadherin表达减弱,细胞间间隙增大,LPS+LXA_4组VE-cadherin、β-catenin mRNA及蛋白水平相对于LPS刺激组表达均上调(*P<0.05),TRPC1的mRNA水平较LPS刺激组低(*P<0.05),VE-cadherin荧光也接近对照组,间隙没有明显增大。
⑸LPS刺激组中ROS的产量高于对照组(*P<0.05),LPS+LXA_4组ROS的产量较LPC刺激组有明显下降(*P<0.05)
⑹与对照组相比,LPS刺激组胞内F340/F380荧光比值明显增高(**P<0.01),LPS+LXA_4组,与LPS刺激组相比,荧光比值下降明显。(**P<0.01)
结论:脂氧素具有减轻LPS所致的内皮细胞通透性增加的作用,其机制可能通过抑制内皮细胞胞内活性氧的产生进而阻断Ca~(2+)信号,防止VE-cadherin/β-catenin解体,来维持内皮细胞之间的紧密连接。
Background: Vascular endothelium ,the largest endocrine organ to regulate the balance in cardiocerebral vascular system, are getting more and more attention.The nomal biological function of endothelial cells will be disordered if they are damaged. The most obvious phenomenon is a mass of increase of vascular endothelial permeability ,which could result in many diseases,like atherogenesis、hypertension、edema caused by preeclampsia. Thus, how to protect endothelial cells from impairment and reduce permeability to a normal level undoubtfully becomes the hot topic in some fields invovled in preventing cardiocerebral vascular diseases.There is no doubt that inflammatory oxidative stress plays a critical role in disfunction of endothelial cells and is able to cause microvascular dysfunction and cardiovascular diseases.Meanwhile, It is well-known that lipoxins are the first endogenous anti-inflammation and pro-resolution chemical substances identified in vivo. Some studies have showed that the level of lipoxins was very low in patients’blood with preeclampsia and hypertension compared with health population.So these evidences strongly suggest that lipoxins probabley exert an important effect of anti-oxidation so as to regulate endothelial permeability.
Objective: To explore how lipoxins could inhibite endothelial hyperpermeability induced by LPS and possible mechanism.
Methods: Human unbilical vein endothelial cell lines (CRL-1730) were cultured and treated with LXA_4 for 30 minutes before stimulation with lipopolysaccharide (LPS). Morphological change of HUVECs was observed by hematoxylin and eosin (H&E); Endothelial permeability was measured by albumin clearance across the monolayer; The production of ROS was detected by ROS kit; the expression of FPRL2 was identified by Real-time PCR, the mRNA expression of VE-cadherin、TRPC1 was tested by RT-PCR; Western blotting method was used to measured the expression of VE-cadherin、β-catenin; Immunofluorescent assay was used to detect the expression of VE-cadherin which was also observed the change of gap size; intracellular Ca~(2+) concentration was determined by Calcium-imaging technology.
Results:⑴The expression of FPRL2 in CRL-1730 cell lines is similar with that in primary HUVECs and LXA_4 could upregulate the expression of FPRL2.
⑵HUCECs became much small、out of shape and cell junctions were destroyed and even emerged very large gap by LPS treatment alone,compared with vehicle group but the morphological change was not obvious in LPS + LXA_4 group.
⑶Compared with control group,endothelial permeability was significantly increased in LPS group (**P<0.01) and the level of permeability was downregulated to the normal by LPS+LXA_4 treatment (**P<0.01), LXA_4 was no dose-dependent manner.
⑷Compared with control group,the mRNA or protein expression of VE-cadherin、β-Catenin were inhibited and the mRNA of TRPC1 was increased by LPS treatment(*P<0.05), meanwhile, all but TRPC1 expressions of them were upregulated by LPS combined with LXA_4 treatment compared with LPS alone(*P<0.05)
⑸The production of ROS was higher by LPS treatment than that without any treatment(*P<0.05), LPS and LXA_4 co-treatment reduced the production of ROS induced by LPS. (*P<0.05)
⑹LXA_4 suppressed the increase of intracellular Ca~(2+) concentration by LPS treatment(**P<0.01).
Conclusions: Lipoxins inhibited endothelial hyperpermeability induced by LPS through decreasing the production of ROS and downregulating Ca~(2+) signaling to suppress disassembly of VE-cadherin/β-Catenin.
目的:探讨脂氧素对脂多糖诱导人脐静脉内皮细胞高通透性的调节及其作用机制。
方法:培养人脐静脉内皮细胞株CRL-1730,实验分为三组:空白对照组,脂多糖(Lipopolysaccharide,LPS)刺激组,脂多糖(LPS)+脂氧素A_4(LXA_4)干预组,苏木精-伊红染色法(Hematoxylin&Eosine,HE)观察细胞的形态变化,单层内皮细胞通透性测定方法测定细胞通透性,活性氧试剂盒检测活性氧(Reactive Oxygen Species,ROS)含量,Real-time PCR检测(Formyl-peptide receptor like 2, FPRL2)受体的表达,RT-PCR法分别检测血管内皮钙粘附素(VE-cadherin)、β-catenin、瞬间受体电位通道(Transient receptor potential channel 1,TRPC1)的mRNA水平,免疫印迹法检测VE-cadherin、β-catenin的蛋白含量,荧光免疫细胞化学法观察VE-cadherin的表达,钙成像技术检测细胞内钙浓度的变化。
结果:⑴. LXA_4刺激后,CRL-1730的FPRL2受体表达与原代HUVEC细胞受体表达量接近且LXA_4能够上调FPRL2的表达。
⑵与对照组相比,LPS刺激组细胞形态变圆且小,细胞与细胞之间间隙变大,LPS+LXA_4组接近正常对照组。
⑶与对照组相比,LPS刺激组细胞的通透性明显增加(**P<0.01).,LPS+LXA_4组能有效的抑制通透性的变化(**P<0.01),但无LXA_4剂量依赖性,LPS+LXA_4+BOC-2组通透性仍然增加(**P<0.05),进一步验证人脐静脉内皮细胞株发挥作用很可能由脂氧素受体FPRL2介导。
⑷与对照组相比,LPS刺激组VE-cadherin、β-catenin的mRNA及蛋白水平均下调,TRPC1的mRNA水平增加(*P<0.05),免疫荧光显示VE-cadherin表达减弱,细胞间间隙增大,LPS+LXA_4组VE-cadherin、β-catenin mRNA及蛋白水平相对于LPS刺激组表达均上调(*P<0.05),TRPC1的mRNA水平较LPS刺激组低(*P<0.05),VE-cadherin荧光也接近对照组,间隙没有明显增大。
⑸LPS刺激组中ROS的产量高于对照组(*P<0.05),LPS+LXA_4组ROS的产量较LPC刺激组有明显下降(*P<0.05)
⑹与对照组相比,LPS刺激组胞内F340/F380荧光比值明显增高(**P<0.01),LPS+LXA_4组,与LPS刺激组相比,荧光比值下降明显。(**P<0.01)
结论:脂氧素具有减轻LPS所致的内皮细胞通透性增加的作用,其机制可能通过抑制内皮细胞胞内活性氧的产生进而阻断Ca~(2+)信号,防止VE-cadherin/β-catenin解体,来维持内皮细胞之间的紧密连接。
Background: Vascular endothelium ,the largest endocrine organ to regulate the balance in cardiocerebral vascular system, are getting more and more attention.The nomal biological function of endothelial cells will be disordered if they are damaged. The most obvious phenomenon is a mass of increase of vascular endothelial permeability ,which could result in many diseases,like atherogenesis、hypertension、edema caused by preeclampsia. Thus, how to protect endothelial cells from impairment and reduce permeability to a normal level undoubtfully becomes the hot topic in some fields invovled in preventing cardiocerebral vascular diseases.There is no doubt that inflammatory oxidative stress plays a critical role in disfunction of endothelial cells and is able to cause microvascular dysfunction and cardiovascular diseases.Meanwhile, It is well-known that lipoxins are the first endogenous anti-inflammation and pro-resolution chemical substances identified in vivo. Some studies have showed that the level of lipoxins was very low in patients’blood with preeclampsia and hypertension compared with health population.So these evidences strongly suggest that lipoxins probabley exert an important effect of anti-oxidation so as to regulate endothelial permeability.
Objective: To explore how lipoxins could inhibite endothelial hyperpermeability induced by LPS and possible mechanism.
Methods: Human unbilical vein endothelial cell lines (CRL-1730) were cultured and treated with LXA_4 for 30 minutes before stimulation with lipopolysaccharide (LPS). Morphological change of HUVECs was observed by hematoxylin and eosin (H&E); Endothelial permeability was measured by albumin clearance across the monolayer; The production of ROS was detected by ROS kit; the expression of FPRL2 was identified by Real-time PCR, the mRNA expression of VE-cadherin、TRPC1 was tested by RT-PCR; Western blotting method was used to measured the expression of VE-cadherin、β-catenin; Immunofluorescent assay was used to detect the expression of VE-cadherin which was also observed the change of gap size; intracellular Ca~(2+) concentration was determined by Calcium-imaging technology.
Results:⑴The expression of FPRL2 in CRL-1730 cell lines is similar with that in primary HUVECs and LXA_4 could upregulate the expression of FPRL2.
⑵HUCECs became much small、out of shape and cell junctions were destroyed and even emerged very large gap by LPS treatment alone,compared with vehicle group but the morphological change was not obvious in LPS + LXA_4 group.
⑶Compared with control group,endothelial permeability was significantly increased in LPS group (**P<0.01) and the level of permeability was downregulated to the normal by LPS+LXA_4 treatment (**P<0.01), LXA_4 was no dose-dependent manner.
⑷Compared with control group,the mRNA or protein expression of VE-cadherin、β-Catenin were inhibited and the mRNA of TRPC1 was increased by LPS treatment(*P<0.05), meanwhile, all but TRPC1 expressions of them were upregulated by LPS combined with LXA_4 treatment compared with LPS alone(*P<0.05)
⑸The production of ROS was higher by LPS treatment than that without any treatment(*P<0.05), LPS and LXA_4 co-treatment reduced the production of ROS induced by LPS. (*P<0.05)
⑹LXA_4 suppressed the increase of intracellular Ca~(2+) concentration by LPS treatment(**P<0.01).
Conclusions: Lipoxins inhibited endothelial hyperpermeability induced by LPS through decreasing the production of ROS and downregulating Ca~(2+) signaling to suppress disassembly of VE-cadherin/β-Catenin.
引文
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