AngⅡ、MAPK、NF-κB在人门静脉高压症脾静脉血管病变中作用的实验研究
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摘要
目的:
研究门静脉高压症(portal hypertension,PHT)脾静脉组织局部血管紧张素II(angiotensin II ,AngII)及其受体表达水平。研究门静脉高压症脾静脉组织中丝裂素活化蛋白激酶(MAPK)、核因子-κB (NF-κB)蛋白的表达。研究AngII以及MAPK、NF-κB与人门静脉高压症脾静脉血管平滑肌细胞(Splenic vein Vascular Smooth Muscle Cell,SvVSMC)增殖的关系。探讨MAPK及NF-κB在AngII诱导的人门静脉高压症SvVSMC增殖中的作用。
方法:
PHT组为乙肝后肝硬化门静脉高压症行脾切除加选择性贲门周围血管离断术患者26例;对照组选取同期因外伤性脾破裂行脾切除术患者10例。放射免疫法(radioimmunoassay,RIA)检测脾静脉中AngII水平;反转录聚合酶链式反应法(RT-PCR法)测定脾静脉血管组织AT1-R及AT2-R mRNA的表达;免疫组织化学法和蛋白免疫印迹法(Western blot)测定NF-κB(p65)、ERK(p-erk42/44)、P38(phospho-p38)蛋白的表达。体外培养人门静脉高压症SvVSMC,用WST-1法测定细胞增殖状况。蛋白免疫印迹法(Western blot)测定人门静脉高压症SvVSMC中NF-κB、ERK、P38蛋白的表达。
结果:
第一部分:
PHT组脾静脉组织AngII为248.91±48.31 ng/L,显著高于对照组AngII为143.35±36.45 ng/L(P<0.01)。免疫组化和蛋白免疫印迹均显示PHT组脾静脉NF-κB、P38、ERK蛋白的表达较对照组明显增强。与对照组比较,PHT组脾静脉AT1-R mRNA表达明显降低(P<0.01)。而AT2-R mRNA表达明显增高(P<0.01)。
第二部分:
1、低浓度AngII(10-8mol/L)促进SvVSMC增殖作用就较显著(P<0.05),随着AngII浓度增高(10~(-7),10-6mol/L),细胞增殖显著上升(P<0.01)。
2、AngII诱导SvVSMC NF-κB蛋白表达,于30min达高峰;在10~(-8)-10~(-6)mol/L浓度范围内,AngII以浓度依赖性方式增加人门静脉高压症SvVSMC的NF-κB活化,当AngII浓度为10~(-7) mol/L时,SvVSMC中的NF-κB表达明显增高,与对照组相比,差异具有极显著统计学意义(P<0.01)。
3、AngII诱导SvVSMC ERK蛋白表达,于10min达高峰,在10~(-8)-10~(-6)mol/L浓度范围内,AngII以浓度依赖性方式增加人门静脉高压症SvVSMC的ERK活化,当AngII浓度为10~(-7) mol/L时,SvVSMC中的ERK表达明显增高,与对照组相比,差异具有极显著统计学意义(P<0.01)。
4、AngII诱导SvVSMC P38蛋白表达,于5min达高峰,在10~(-8)-10~(-6)mol/L浓度范围内,AngII以浓度依赖性方式增加人PHT脾静脉VSMC的P38活化,当AngII浓度为10~(-7) mol/L时,SvVSMC中的P38表达明显增高,与对照组相比,差异具有极显著统计学意义(P<0.01)。
5、NF-κB特异性阻断剂PDTC(100umol/L)降低AngII(10~(-7)mol/L)诱导的SvVSMC NF-κB活性和细胞增殖,与单纯AngII(10~(-7)mol/L)组比较,差异有统计学意义(P<0.01);与单纯AngII(10~(-7)mol/L)组比较,ERK特异性阻断剂PD98059(100umol/L)降低AngII(10~(-7)mol/L)诱导的SvVSMC ERK活性和细胞增殖,差异有统计学意义(P<0.01);P38特异性阻断剂SB202190(10~(-7) mol/L)降低AngII(10~(-7)mol/L)诱导的SvVSMC P38活性和细胞增殖,与单纯AngII(10~(-7)mol/L)组比较,差异有统计学意义(P<0.01);JNK特异性阻断剂SP600125(100umol/L)能降低AngII(10~(-7)mol/L)诱导的人PHT脾静脉VSMC的细胞增殖,与单纯AngII组比较,差异有统计学意义(P<0.01)。PD98059、PDTC干预后AngII(10~(-7)mol/L)诱导SvVSMC WST-1活性与对照组相比无明显统计学差异(P>0.05),而SB202190、SP600125干预后AngII诱导人PHT脾静脉WST-1活性与对照组相比存在显著差异(P<0.05)。
6、PD98059(100umol/L)干预后AngII(10~(-7)mol/L)诱导的SvVSMC NF-κB活性与单纯AngI(I10~(-7)mol/L)组比较显著降低(P<0.01);与单纯AngI(I10~(-7)mol/L)组比较,SB202190(10~(-7) mol/L)干预后AngII(10~(-7)mol/L)诱导的SvVSMC P38活性显著降低(P<0.01);SP600125(100umol/L)干预后AngII(10~(-7)mol/L)诱导的SvVSMC NF-κB活性与单纯AngII(10~(-7)mol/L)组比较显著降低(P<0.01);PDTC(100umol/L)干预后,AngII(10~(-7)mol/L)诱导的SvVSMC P38活性与单纯AngII(10~(-7)mol/L)组比较显著降低(P<0.01)。
结论:
第一部分:1.门静脉高压症脾静脉血管存在LRAS的激活,提示LRAS的激活可能参与PHT时的脾静脉血管病变的形成和发展。2.门静脉高压症时脾静脉血管NF-κB、ERK及P38活化可能与门静脉脉高压症血管病变关系密切。3.门静脉高压症时脾静脉血管LRAS的激活可能是脾静脉血管中NF-κB、ERK及P38活化的重要原因。
第二部分:1. AngII诱导SvVSMC中MAPK、NF-κB活化是促人PHT SvVSMC增殖的重要原因。2. ERK、NF-κB途径是AngII诱导人PHT SvVSMC增殖的主要途径。3. AngII诱导人PHT SvVSMC MAPK活化可以激活NF-κB。4. AngII诱导人PHT SvVSMC NF-κB活化可以激活P38. 5. AngII激活MAPK、NF-κB通路可能是门静脉高压症血管病变发生发展的重要原因。
Objective: My project aims to investigate the expression levels of local angiotensin II (AngII) and its receptors, mitogen-activated protein kinase(MAPK) and nuclear factor-kappa B(NF-κB) in splenic vein of portal hypertension (PHT) patients. The roles AngII, MAPK and NF-κB in the proliferation of human Splenic vein Vascular Smooth Muscle Cel(lSvVSMC)of PHT patients will also be investigated. In the end, the effects of MAPK and NF-κB on the proliferation of human SvVSMC of portal hypertension induced by angiotensin II.
Method: Twenty-six patients with posthepatitic cirrhosis portal hypertension(18 males and 8 females) admitted to the First Affiliated Hospital of Fujian Medical University were subjected to splenectomy plus pericardial devascularization during hospitalization served as PHT group, and 10 patients(7 males and 3 females) with traumatic spleen rupture subject to splenectomy during the same period as the control group. Radioimmunoasasy (RIA) was used to determine the AngII level in Splenic Vein. The mRNA expression of AT1-RmRNA、AT2-R in splenic vein was detected by RT-PCR. The protein expression of NF-κB(p65), ERK(p-erk 42/44) and P38(phospho-p38) in Splenic Veins was determined by immunohistochemistry and western blot. SvVSMC were obtained from human splenic vein of PHT patients. WST-1 was used to measure the proliferation activity of VSMC. The protein expression of NF-κB, ERK and P38 in SvVSMC was assayed by western blot.
Result:
Part I: Compared to the control group, in the splenic veins of the PHT group, the expression level of local AngII was significantly higher (248.91±48.31) ng/L vs (143.35±36.45) ng/L(P<0.01), the protein expression of NF-κB, P38 and ERK was stronger (P<0.01) and the mRNA level of AT2-R increased (P<0.01), whereas the mRNA level of AT1-R dramatically reduced (P<0.01).
Part II
1. AngII(10~(-8)-10~(-6)mol/L) increased NF-κB activity in SvVSMC in a dose-dependent manner.
2. AngII increased the protein expression of NF-κB in human PHT SvVSMC, which peaked 30 minutes after stimulation. Within the range of 10~(-8)-10~(-6)mol/L, AngII increased the proliferation activity (WST-1) of SvVSMC with markedly statistics difference (P<0.05) compared with control.
3. AngII increased the protein expression of ERK in human PHT SvVSMC, which peaked 10 minutes after stimulation. Within the range of 10~(-8)-10~(-6)mol/L, AngII increased ERK activity in human PHT SvVSMC in a dose-dependent manner. Compared with control, AngII(10~(-8)-10~(-6)mol/L) increased the proliferation activity of SvVSMC with markedly statistics difference(P<0.05)
4. AngII increased the protein expression of p38 in human PHT SvVSMC, which peaked 5 minutes after stimulation. Within the range of 10~(-8)-10~(-6)mol/L,, AngII(10~(-8)-10~(-6)mol/L) increased P38 activity in SvVSMC in a dose-dependent manner. AngII(10~(-8)-10~(-6)mol/L) increased the proliferation activity (WST-1) of human PHT SvVSMC with markedly statistics difference(P<0.05 or P<0.01) compared with control
5. Compared to the AngII (10~(-7)mol/L) only treatment, the addition of the selective NF-κB antagonist PDTC(100umol/L), the selective ERK antagonist PD98059(100umol/L), the selective p38 antagonist SB202190 (10~(-7)mol/L) and the selective JNK antagonist SP600125(100umol/L)decreased the proliferation of SvVSMC stimulated by AngII (P<0.01). Blocked with PD98059 or PDTC,the proliferation of SvVSMC stimulated by AngII compared with control group demonstrated no significant difference (P>0.05). However, blocked with SB202190 or SP600125, the proliferation of SvVSMC stimulated by AngII(10~(-7)mol/L), compared with control group still illustrated significant difference ( P<0.05).
6. Compared to the AngII (10~(-7)mol/L) only treatment, in SvVSMC stimulated by AngII (10~(-7)mol/L), the addition of PD98059 ( 100umol/L ) , SB202190(10~(-7)mol/L) and SP600125(100umol/L)decreased the activity of NF-κB (P<0.01), whereas PDTC decreased the activity of P38 (P<0.01).
Conclusion:
Part I: During PHT,LRAS in splenic vein was activated and the expression of NF-κB, ERK and P38 increased. Therefore, LRAS, MAPK, NF-κB may be critical for the development of the pathological changes of PHT.
Part II: AngII can stimulate the proliferation of human PHT SvVSMC. AngII can activate NF-κB、ERK、P38 in the SvVSMC. In the proliferation of SvVSMC induced by AngII, NF-κB and ERK pathways are more important than P38 and ERK pathway. Activation of MAPK in the SvVSMC by AngII activates NF-κB. Activation of NF-κB in the VSMC by AngII activates p38, but not ERK. AngII may be critical for the formation and maintenance of PHT because during PHT, AngII may participate in the development of the pathological changes of the veins by activating the MAPK and NF-kB signaling pathways, which will lead to a series of subsequent effects such as the proliferation of the vascular smooth muscle cells.
研究门静脉高压症(portal hypertension,PHT)脾静脉组织局部血管紧张素II(angiotensin II ,AngII)及其受体表达水平。研究门静脉高压症脾静脉组织中丝裂素活化蛋白激酶(MAPK)、核因子-κB (NF-κB)蛋白的表达。研究AngII以及MAPK、NF-κB与人门静脉高压症脾静脉血管平滑肌细胞(Splenic vein Vascular Smooth Muscle Cell,SvVSMC)增殖的关系。探讨MAPK及NF-κB在AngII诱导的人门静脉高压症SvVSMC增殖中的作用。
方法:
PHT组为乙肝后肝硬化门静脉高压症行脾切除加选择性贲门周围血管离断术患者26例;对照组选取同期因外伤性脾破裂行脾切除术患者10例。放射免疫法(radioimmunoassay,RIA)检测脾静脉中AngII水平;反转录聚合酶链式反应法(RT-PCR法)测定脾静脉血管组织AT1-R及AT2-R mRNA的表达;免疫组织化学法和蛋白免疫印迹法(Western blot)测定NF-κB(p65)、ERK(p-erk42/44)、P38(phospho-p38)蛋白的表达。体外培养人门静脉高压症SvVSMC,用WST-1法测定细胞增殖状况。蛋白免疫印迹法(Western blot)测定人门静脉高压症SvVSMC中NF-κB、ERK、P38蛋白的表达。
结果:
第一部分:
PHT组脾静脉组织AngII为248.91±48.31 ng/L,显著高于对照组AngII为143.35±36.45 ng/L(P<0.01)。免疫组化和蛋白免疫印迹均显示PHT组脾静脉NF-κB、P38、ERK蛋白的表达较对照组明显增强。与对照组比较,PHT组脾静脉AT1-R mRNA表达明显降低(P<0.01)。而AT2-R mRNA表达明显增高(P<0.01)。
第二部分:
1、低浓度AngII(10-8mol/L)促进SvVSMC增殖作用就较显著(P<0.05),随着AngII浓度增高(10~(-7),10-6mol/L),细胞增殖显著上升(P<0.01)。
2、AngII诱导SvVSMC NF-κB蛋白表达,于30min达高峰;在10~(-8)-10~(-6)mol/L浓度范围内,AngII以浓度依赖性方式增加人门静脉高压症SvVSMC的NF-κB活化,当AngII浓度为10~(-7) mol/L时,SvVSMC中的NF-κB表达明显增高,与对照组相比,差异具有极显著统计学意义(P<0.01)。
3、AngII诱导SvVSMC ERK蛋白表达,于10min达高峰,在10~(-8)-10~(-6)mol/L浓度范围内,AngII以浓度依赖性方式增加人门静脉高压症SvVSMC的ERK活化,当AngII浓度为10~(-7) mol/L时,SvVSMC中的ERK表达明显增高,与对照组相比,差异具有极显著统计学意义(P<0.01)。
4、AngII诱导SvVSMC P38蛋白表达,于5min达高峰,在10~(-8)-10~(-6)mol/L浓度范围内,AngII以浓度依赖性方式增加人PHT脾静脉VSMC的P38活化,当AngII浓度为10~(-7) mol/L时,SvVSMC中的P38表达明显增高,与对照组相比,差异具有极显著统计学意义(P<0.01)。
5、NF-κB特异性阻断剂PDTC(100umol/L)降低AngII(10~(-7)mol/L)诱导的SvVSMC NF-κB活性和细胞增殖,与单纯AngII(10~(-7)mol/L)组比较,差异有统计学意义(P<0.01);与单纯AngII(10~(-7)mol/L)组比较,ERK特异性阻断剂PD98059(100umol/L)降低AngII(10~(-7)mol/L)诱导的SvVSMC ERK活性和细胞增殖,差异有统计学意义(P<0.01);P38特异性阻断剂SB202190(10~(-7) mol/L)降低AngII(10~(-7)mol/L)诱导的SvVSMC P38活性和细胞增殖,与单纯AngII(10~(-7)mol/L)组比较,差异有统计学意义(P<0.01);JNK特异性阻断剂SP600125(100umol/L)能降低AngII(10~(-7)mol/L)诱导的人PHT脾静脉VSMC的细胞增殖,与单纯AngII组比较,差异有统计学意义(P<0.01)。PD98059、PDTC干预后AngII(10~(-7)mol/L)诱导SvVSMC WST-1活性与对照组相比无明显统计学差异(P>0.05),而SB202190、SP600125干预后AngII诱导人PHT脾静脉WST-1活性与对照组相比存在显著差异(P<0.05)。
6、PD98059(100umol/L)干预后AngII(10~(-7)mol/L)诱导的SvVSMC NF-κB活性与单纯AngI(I10~(-7)mol/L)组比较显著降低(P<0.01);与单纯AngI(I10~(-7)mol/L)组比较,SB202190(10~(-7) mol/L)干预后AngII(10~(-7)mol/L)诱导的SvVSMC P38活性显著降低(P<0.01);SP600125(100umol/L)干预后AngII(10~(-7)mol/L)诱导的SvVSMC NF-κB活性与单纯AngII(10~(-7)mol/L)组比较显著降低(P<0.01);PDTC(100umol/L)干预后,AngII(10~(-7)mol/L)诱导的SvVSMC P38活性与单纯AngII(10~(-7)mol/L)组比较显著降低(P<0.01)。
结论:
第一部分:1.门静脉高压症脾静脉血管存在LRAS的激活,提示LRAS的激活可能参与PHT时的脾静脉血管病变的形成和发展。2.门静脉高压症时脾静脉血管NF-κB、ERK及P38活化可能与门静脉脉高压症血管病变关系密切。3.门静脉高压症时脾静脉血管LRAS的激活可能是脾静脉血管中NF-κB、ERK及P38活化的重要原因。
第二部分:1. AngII诱导SvVSMC中MAPK、NF-κB活化是促人PHT SvVSMC增殖的重要原因。2. ERK、NF-κB途径是AngII诱导人PHT SvVSMC增殖的主要途径。3. AngII诱导人PHT SvVSMC MAPK活化可以激活NF-κB。4. AngII诱导人PHT SvVSMC NF-κB活化可以激活P38. 5. AngII激活MAPK、NF-κB通路可能是门静脉高压症血管病变发生发展的重要原因。
Objective: My project aims to investigate the expression levels of local angiotensin II (AngII) and its receptors, mitogen-activated protein kinase(MAPK) and nuclear factor-kappa B(NF-κB) in splenic vein of portal hypertension (PHT) patients. The roles AngII, MAPK and NF-κB in the proliferation of human Splenic vein Vascular Smooth Muscle Cel(lSvVSMC)of PHT patients will also be investigated. In the end, the effects of MAPK and NF-κB on the proliferation of human SvVSMC of portal hypertension induced by angiotensin II.
Method: Twenty-six patients with posthepatitic cirrhosis portal hypertension(18 males and 8 females) admitted to the First Affiliated Hospital of Fujian Medical University were subjected to splenectomy plus pericardial devascularization during hospitalization served as PHT group, and 10 patients(7 males and 3 females) with traumatic spleen rupture subject to splenectomy during the same period as the control group. Radioimmunoasasy (RIA) was used to determine the AngII level in Splenic Vein. The mRNA expression of AT1-RmRNA、AT2-R in splenic vein was detected by RT-PCR. The protein expression of NF-κB(p65), ERK(p-erk 42/44) and P38(phospho-p38) in Splenic Veins was determined by immunohistochemistry and western blot. SvVSMC were obtained from human splenic vein of PHT patients. WST-1 was used to measure the proliferation activity of VSMC. The protein expression of NF-κB, ERK and P38 in SvVSMC was assayed by western blot.
Result:
Part I: Compared to the control group, in the splenic veins of the PHT group, the expression level of local AngII was significantly higher (248.91±48.31) ng/L vs (143.35±36.45) ng/L(P<0.01), the protein expression of NF-κB, P38 and ERK was stronger (P<0.01) and the mRNA level of AT2-R increased (P<0.01), whereas the mRNA level of AT1-R dramatically reduced (P<0.01).
Part II
1. AngII(10~(-8)-10~(-6)mol/L) increased NF-κB activity in SvVSMC in a dose-dependent manner.
2. AngII increased the protein expression of NF-κB in human PHT SvVSMC, which peaked 30 minutes after stimulation. Within the range of 10~(-8)-10~(-6)mol/L, AngII increased the proliferation activity (WST-1) of SvVSMC with markedly statistics difference (P<0.05) compared with control.
3. AngII increased the protein expression of ERK in human PHT SvVSMC, which peaked 10 minutes after stimulation. Within the range of 10~(-8)-10~(-6)mol/L, AngII increased ERK activity in human PHT SvVSMC in a dose-dependent manner. Compared with control, AngII(10~(-8)-10~(-6)mol/L) increased the proliferation activity of SvVSMC with markedly statistics difference(P<0.05)
4. AngII increased the protein expression of p38 in human PHT SvVSMC, which peaked 5 minutes after stimulation. Within the range of 10~(-8)-10~(-6)mol/L,, AngII(10~(-8)-10~(-6)mol/L) increased P38 activity in SvVSMC in a dose-dependent manner. AngII(10~(-8)-10~(-6)mol/L) increased the proliferation activity (WST-1) of human PHT SvVSMC with markedly statistics difference(P<0.05 or P<0.01) compared with control
5. Compared to the AngII (10~(-7)mol/L) only treatment, the addition of the selective NF-κB antagonist PDTC(100umol/L), the selective ERK antagonist PD98059(100umol/L), the selective p38 antagonist SB202190 (10~(-7)mol/L) and the selective JNK antagonist SP600125(100umol/L)decreased the proliferation of SvVSMC stimulated by AngII (P<0.01). Blocked with PD98059 or PDTC,the proliferation of SvVSMC stimulated by AngII compared with control group demonstrated no significant difference (P>0.05). However, blocked with SB202190 or SP600125, the proliferation of SvVSMC stimulated by AngII(10~(-7)mol/L), compared with control group still illustrated significant difference ( P<0.05).
6. Compared to the AngII (10~(-7)mol/L) only treatment, in SvVSMC stimulated by AngII (10~(-7)mol/L), the addition of PD98059 ( 100umol/L ) , SB202190(10~(-7)mol/L) and SP600125(100umol/L)decreased the activity of NF-κB (P<0.01), whereas PDTC decreased the activity of P38 (P<0.01).
Conclusion:
Part I: During PHT,LRAS in splenic vein was activated and the expression of NF-κB, ERK and P38 increased. Therefore, LRAS, MAPK, NF-κB may be critical for the development of the pathological changes of PHT.
Part II: AngII can stimulate the proliferation of human PHT SvVSMC. AngII can activate NF-κB、ERK、P38 in the SvVSMC. In the proliferation of SvVSMC induced by AngII, NF-κB and ERK pathways are more important than P38 and ERK pathway. Activation of MAPK in the SvVSMC by AngII activates NF-κB. Activation of NF-κB in the VSMC by AngII activates p38, but not ERK. AngII may be critical for the formation and maintenance of PHT because during PHT, AngII may participate in the development of the pathological changes of the veins by activating the MAPK and NF-kB signaling pathways, which will lead to a series of subsequent effects such as the proliferation of the vascular smooth muscle cells.
引文
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3. Yali Z, Jie L, Li L,et al. Role of Ras/PKCzeta/MEK/ERK1/2 signaling pathway in angiotensin II-induced vascular smooth muscle cell proliferation. Regulatory Peptides , 2005 ,128: 43–50.
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13. Tamura K,Chen YE. Molecular mechanism of fibronectin gene activation by cyclic stretch in vascular smooth muscle cells. J Biol Chem, 2000, 275(44): 34 619-627
14. Touyz RM, He G. P38 MAP kinase regulates vascular smooth muscle cell collagen synthesis by angiotensin II in SHR but not in WKY. Hypertension, 2001, 37(2 part 2): 574-580
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21. Serafim Kiriakidis , Evangelos Andreakos. VEGF expression in human macrophages is NF-κB dependeng:studies using ade-novriuses expressing the endogenous NF-κB inhibitor IκBα and a kinase-defective form of the IκB kinase2. Journal of Cell Science,2003,116(4):665-674
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23. Tak PP , Firestein GS. NF-kappaB: a key role in inflammatory diseases . JClin Invest , 2001, 107(1): 7-11
24. Baldwin AS Jr. Series introduction: the transcription factor NF-kappaB and human disease. J Clin Inves t, 2001 , 107(1): 3-6
25. Peng JF,Devorah Gurantz,Van Tran,et al. Tumor necrosis factor-α induced AT1 receptor upregulation enhances angiotesin II mediated cardiac fibroblast responses that facor fibrosis.Circ Res, 2002, 91: 1119-1126
26. Chen K, Vita A.C-Jun N-terminal Kinase activation by hydrogen peroxide in endothelial cells involves Src-dependent epidermal growth factor receptor transactivation.J Biol Chem.2001.276:16045-16050
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