NF-κB信号传导途径在门静脉高压性血管病变发生中作用的研究
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摘要
目的:通过对门静脉高压症(portal hypertension,PHT)病人脾脏动、静脉壁核因子-κappa B(NF-κB)的活性检测及血管紧张素原、肿瘤坏死因子-α(TNF-α)、基质Gla蛋白(matrix Gla protein,MGP) mRNA的表达检测,探讨门静脉高压症时NF-κB信号传导途径在门静脉高压性血管病变发生中的作用。
方法:用化学发光凝胶电泳迁移率实验(EMSA)方法检测门静脉高压症病人脾脏动、静脉壁NF-κB的活性;采用逆转录-聚合酶链反应(RT-PCR)方法检测肝硬化门静脉高压症病人脾脏动、静脉壁和正常血管壁局部血管紧张素原、肿瘤坏死因子-α、基质Gla蛋白mRNA的表达情况;光镜及电镜观察PHT脾脏动、静脉病理形态学改变。
结果:脾破裂对照组脾脏动、静脉内NF-κB未见显著活化,仅检测到微量活性的NF-κB表达,分别为(0.19±0.20)、(0.25±0.16);而于PHT组病人脾脏动、静脉内则检测到显著具有活性的NF-κB表达,分别为(1.44±0.23)、(1.38±0.18),与对照组相比存在显著性差异(P<0.05)。对照组内脾脏动、静脉组织局部血管紧张素原mRNA分别为(0.23±0.12)、(0.18±0.10),显著低于肝硬化门静脉高压症组脾动脉、脾静脉组织局部血管紧张素原mRNA的表达(0.48±0.21)、(0.43±0.16),(P<0.05);对照组内脾脏动、静脉组织TNF-αmRNA分别为(0.24±0.12)、(0.21±0.10),显著低于肝硬化PHT组脾动脉、脾静脉TNF-αmRNA的表达(0.38±0.21)、(0.36±0.16),(P<0.05),且PHT组脾脏动、静脉TNF-αmRNA表达与NF-κB的活性呈显著的正相关;对照组内脾脏动、静脉组织MGP mRNA分别为(0.23±0.10)、(0.26±0.13),显著低于PHT组脾动脉、脾静脉MGP mRNA的表达(0.58±0.19)、(0.55±0.15),(P<0.05)。光镜与电镜观察下与对照组脾脏血管相比,PHT组的脾脏血管均存在不同程度的平滑肌细胞增生、肥大以及与生物合成有关的细胞器增多。
结论:NF-κB信号传导途径与门静脉高压症时内脏血管病变的发生有关;肝硬化门静脉高压病人局部血管紧张素原mRNA、肿瘤坏死因子-α、基质Gla蛋白mRNA表达增强,NF-κB的活化,可能是肝硬化门静脉高压症时内脏血管病变形成和发展的原因之一。
Objective:The present study was designed to investigate the activation of local nuclear factor-Kappa B(NF-κB) and the expression of local angiotensinogen, tumor necrosis factor alpha(TNF-α) and matrix Gla protein(MGP) mRNA in splenic artery and vein of portal hypertensive patients and to discuss Role of nuclear factor- Kappa B signal transduction pathway in the pathogenesis of portal hypertensive vasculopathy.
Method:Chemiluminescent electrophoretic mobility shift assay(EMSA) was used to detect the activation of NF-κB in splenic artery and vein of portal hypertensive patients and normal vascular. The expression of local angiotensinogen, tumor necrosis factor alpha(TNF-α) and matrix Gla protein(MGP) mRNA in splenic artery and vein of portal hypertensive patients and normal vascular were detected by RT-PCR analysis. Splenic artery and vein of portal hypertensive patients and normal vascular were observed under optic and electron microscopes.
Results:The activation of NF-κB in splenic artry and vein of portal hypertensive patients(1.44±0.23)、(1.38±0.18) was observed significantly higher than that in control group(0.19±0.20)、(0.25±0.16)(P<0.05). Levels of local angiotensinogen mRNA in splenic artery and vein of portal hypertensive grpup were (0.48±0.21)、(0.43±0.16), Respectively significantly higher than that in control group(0.23±0.12、0.18±0.10)(all P<0.05). Expression of TNF-αmRNA in splenic artery and vein of portal hypertensive group was (0.38±0.21)、(0.36±0.16),respectively, significantly higher than that in control group(0.24±0.12、0.21±0.10)(all P<0.05), and the expression of TNF-αmRNA in splenic artery and vein of portal hypertensive patients had a significant positive correlation with the activity of NF-κB(r=0.796,P<0.05;r=0.849,P<0.05, respectively). Expression of MGP mRNA in splenic artery and vein of portal hypertensive group was (0.58±0.19)、(0.55±0.15),respectively,significantly higher than that in control group(0.23±0.10、0.26±0.13 )(all P<0.05). There was no significant difference between the splenic artery and vein in the expression of local angiotensinogen, TNF-αand MGP mRNA in portal hypertensive group. Compare with normal vascular we found a large number of hypertrophic and proliferative smooth muscle cells in the Splenic artery and vein of portal hypertensive patients,some of them migrated to the subintima;cell organ pert biosynthesis increased.
Conclusion:The activation of NF-κB increased in splenic artry and vein of portal hypertensive patients,which indicated that NF-κB signal transduction pathway may play an important role in the pathogenesis of portal hypertensive vasculopathy. Local angiotensinogen and TNF-αand activation of NF-κB maybe the factors in the pathogenesis of portal hypertensive vasculopathy,which can cause and to advance portal hypertensive vasculopathy.Significant expression of MGP mRNA in splenic artery and vein of PHT can regulate proliferation and migration of the vascular smooth muscle cell(VSMC),and MGP was the marker gene of VSMC phenotype,which can also cause and to advance portal hypertensive vasculopathy.
方法:用化学发光凝胶电泳迁移率实验(EMSA)方法检测门静脉高压症病人脾脏动、静脉壁NF-κB的活性;采用逆转录-聚合酶链反应(RT-PCR)方法检测肝硬化门静脉高压症病人脾脏动、静脉壁和正常血管壁局部血管紧张素原、肿瘤坏死因子-α、基质Gla蛋白mRNA的表达情况;光镜及电镜观察PHT脾脏动、静脉病理形态学改变。
结果:脾破裂对照组脾脏动、静脉内NF-κB未见显著活化,仅检测到微量活性的NF-κB表达,分别为(0.19±0.20)、(0.25±0.16);而于PHT组病人脾脏动、静脉内则检测到显著具有活性的NF-κB表达,分别为(1.44±0.23)、(1.38±0.18),与对照组相比存在显著性差异(P<0.05)。对照组内脾脏动、静脉组织局部血管紧张素原mRNA分别为(0.23±0.12)、(0.18±0.10),显著低于肝硬化门静脉高压症组脾动脉、脾静脉组织局部血管紧张素原mRNA的表达(0.48±0.21)、(0.43±0.16),(P<0.05);对照组内脾脏动、静脉组织TNF-αmRNA分别为(0.24±0.12)、(0.21±0.10),显著低于肝硬化PHT组脾动脉、脾静脉TNF-αmRNA的表达(0.38±0.21)、(0.36±0.16),(P<0.05),且PHT组脾脏动、静脉TNF-αmRNA表达与NF-κB的活性呈显著的正相关;对照组内脾脏动、静脉组织MGP mRNA分别为(0.23±0.10)、(0.26±0.13),显著低于PHT组脾动脉、脾静脉MGP mRNA的表达(0.58±0.19)、(0.55±0.15),(P<0.05)。光镜与电镜观察下与对照组脾脏血管相比,PHT组的脾脏血管均存在不同程度的平滑肌细胞增生、肥大以及与生物合成有关的细胞器增多。
结论:NF-κB信号传导途径与门静脉高压症时内脏血管病变的发生有关;肝硬化门静脉高压病人局部血管紧张素原mRNA、肿瘤坏死因子-α、基质Gla蛋白mRNA表达增强,NF-κB的活化,可能是肝硬化门静脉高压症时内脏血管病变形成和发展的原因之一。
Objective:The present study was designed to investigate the activation of local nuclear factor-Kappa B(NF-κB) and the expression of local angiotensinogen, tumor necrosis factor alpha(TNF-α) and matrix Gla protein(MGP) mRNA in splenic artery and vein of portal hypertensive patients and to discuss Role of nuclear factor- Kappa B signal transduction pathway in the pathogenesis of portal hypertensive vasculopathy.
Method:Chemiluminescent electrophoretic mobility shift assay(EMSA) was used to detect the activation of NF-κB in splenic artery and vein of portal hypertensive patients and normal vascular. The expression of local angiotensinogen, tumor necrosis factor alpha(TNF-α) and matrix Gla protein(MGP) mRNA in splenic artery and vein of portal hypertensive patients and normal vascular were detected by RT-PCR analysis. Splenic artery and vein of portal hypertensive patients and normal vascular were observed under optic and electron microscopes.
Results:The activation of NF-κB in splenic artry and vein of portal hypertensive patients(1.44±0.23)、(1.38±0.18) was observed significantly higher than that in control group(0.19±0.20)、(0.25±0.16)(P<0.05). Levels of local angiotensinogen mRNA in splenic artery and vein of portal hypertensive grpup were (0.48±0.21)、(0.43±0.16), Respectively significantly higher than that in control group(0.23±0.12、0.18±0.10)(all P<0.05). Expression of TNF-αmRNA in splenic artery and vein of portal hypertensive group was (0.38±0.21)、(0.36±0.16),respectively, significantly higher than that in control group(0.24±0.12、0.21±0.10)(all P<0.05), and the expression of TNF-αmRNA in splenic artery and vein of portal hypertensive patients had a significant positive correlation with the activity of NF-κB(r=0.796,P<0.05;r=0.849,P<0.05, respectively). Expression of MGP mRNA in splenic artery and vein of portal hypertensive group was (0.58±0.19)、(0.55±0.15),respectively,significantly higher than that in control group(0.23±0.10、0.26±0.13 )(all P<0.05). There was no significant difference between the splenic artery and vein in the expression of local angiotensinogen, TNF-αand MGP mRNA in portal hypertensive group. Compare with normal vascular we found a large number of hypertrophic and proliferative smooth muscle cells in the Splenic artery and vein of portal hypertensive patients,some of them migrated to the subintima;cell organ pert biosynthesis increased.
Conclusion:The activation of NF-κB increased in splenic artry and vein of portal hypertensive patients,which indicated that NF-κB signal transduction pathway may play an important role in the pathogenesis of portal hypertensive vasculopathy. Local angiotensinogen and TNF-αand activation of NF-κB maybe the factors in the pathogenesis of portal hypertensive vasculopathy,which can cause and to advance portal hypertensive vasculopathy.Significant expression of MGP mRNA in splenic artery and vein of PHT can regulate proliferation and migration of the vascular smooth muscle cell(VSMC),and MGP was the marker gene of VSMC phenotype,which can also cause and to advance portal hypertensive vasculopathy.
引文
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1. Sen R,Baltimore D.Multipe nuclear factors interact with the immunoglobulin enhancer sequences .Cell,1986,46:705-716.
2. Muller DN,,Nervaala EM, Dechend R, et al. Angiotensin II(AT1)receptor blockade reduces vascular tissue factor in angiotensinII-induced cardiac vasculopathy. Am J Pathol, 2000, 157(1):111-122.
3. Cominacini L, Crarbin V, Pasini AF, et al. The expression of adhesion molecules on endothelial cells in inhibited by troglitazone through its antioxidant activity . Cell Adhes Gommun,1999,7(3):223-231.
4. Speir E. Cytomegalovins gene regulation by reactive oxygen species . Agents in Atherosclerosis . Ann NY Acad Sci,2000,899 (3):363-374.
5. Siebenlist U, Franzoso G, Brown K. Structure,regulation and function of NF-kappa B.Annu Rev Cell Biol, 1994, 10(2):405-455.
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