尾加压素Ⅱ对血管外膜成纤维细胞表达单核细胞趋化蛋白-1的作用及机制研究
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摘要
背景:尾加压素II(urotensin II, UII)是由11个氨基酸残基组成的生长抑素样神经环肽,最早从硬骨鱼脊髓尾部下垂体(urophysis)中分离出来,其活性中心氨基酸序列从鱼到人高度保守。GPR14为其特异性受体,亦称为UT receptor(UT),UII及其受体广泛分布于心血管、肺、中枢神经系统和肾脏等。UII是迄今为止所发现的作用最强的内源性血管收缩肽,具有许多生理学效应,例如刺激血管平滑肌细胞、成纤维细胞和癌细胞增殖,促进泡沫细胞的形成、促进心肌肥大、影响其收缩性,此外,对炎性细胞还有趋化作用,参与了多种心血管疾病的发生和发展。目前研究表明,炎性机制是许多心血管疾病如动脉粥样硬化、心肌肥大、心功能衰竭等发生发展的重要机制之一,其中血管外膜成纤维细胞是参与血管炎症启始的重要细胞之一,而单核细胞趋化蛋白-1(MCP-1)参与心血管系统疾病炎性发展过程的重要活性因子之一。然而UII对血管外膜成纤维细胞表达MCP-1的作用和机制尚不清楚。
目的:观察尾加压素II对血管外膜成纤维细胞(AFs)的MCP-1表达的影响,并进一步研究其细胞内信号转导机制。
方法:①用组织贴块法培养SD大鼠的AFs,用不同浓度的UII(10-10-10-7mol/L)刺激AFs不同时间,然后用逆转录-聚合酶链反应(RT-PCR)及Western印迹法检测MCP-1基因和蛋白的表达,用ELISA法检测MCP-1的胞外分泌情况。②用各细胞内信号转导通路阻断剂预处理AFs 30min,然后用UII (10-8mol/L)刺激AFs 3h和12h,分别从基因水平和蛋白分泌水平观察细胞MCP-1的表达和分泌情况。
结果:UII可呈浓度依赖性地上调MCP-1 mRNA和蛋白的表达,与对照组相比差异均有统计学意义(P值均<0.05),10-8mol/L时达到峰值(P<0.01)。UII的最佳刺激时间点在基因和蛋白水平上分别为3小时和24小时,在蛋白的胞外分泌水平上为12小时。UII的这种刺激MCP-1分泌的作用可以被UII受体阻断剂SB710411、Rho激酶阻断剂Y27632、蛋白激酶C(PKC)阻断剂H-7、促有丝分裂蛋白激酶(MAPK)阻断剂PD98059、钙调神经磷酸酶(CaN)阻断剂Cyclosporine A和钙通道阻断剂Nicardipine所抑制,抑制率分别为64.23%、39.14%、70.76%、68.31%、65.92%和63.47%(P值均<0.01)
结论:UII呈浓度依赖性地促进血管外膜成纤维细胞表达单核细胞趋化蛋白-1,这一作用可通过PKC、MAPK、钙通道、CaN以及Rho信号途径来实现。
Background: Human Urotensin II (UII) is an 11 amino acid cyclic peptide originally isolated from the goby fish. The amino acid sequence of UII is exceptionally conserved across most vertebrate taxa, sharing structural similarity to somatostatin. UII binds to a class of G-protein coupled receptor known as GPR14 or the urotensin receptor (UT). UII and its receptor UT are widely expressed throughout the cardiovascular, pulmonary, central nervous, renal and metabolic systems. UII is generally agreed to be the most potent endogenous vasoconstrictor discovered to date. UII also exerts a wide range of actions in other systems such as proliferation of vascular smooth muscle cells, fibroblasts and cancer cells. It also enhances foam cell formation, chemotaxis of inflammatory cells, inotropic and hypertrophic effects on heart muscle. Many of the major diseases, including cardiovascular disease, such as atherosclerosis, cardiac hypertrophy and heart failure, are widely recognized as inflammatory diseases. Many research support that adventitial fibroblasts may be an early event with a significant role during the development of vascular inflammatory diseases. Monocyte chemoattractant protein-1 (MCP-1) plays a critical role in the development of cardiovascular diseases. But, its mechanisms of urotensin II on the expression of monocyte chemoattractant protein-1 in rat aortic adventitial fibroblasts are discorvered.
Objective: To investigate the effect of urotensin II(UII) on the expression of monocyte chemoattractant protein-1 in rat aortic adventitial fibroblasts, and to study the signal transduction pathways.
Methods:①In cultured adventitial fibroblasts isolated from aorta of adult Sprague-Dawley rats, Growth-arrested adventitial fibroblasts were incubated in serum-free medium with urotensin II (10-10-10-7mol/L) for different lengths time(1h, 3h, 6h, 12h, 24h). Then RT-PCR and Western Blotting was used to detect the expression of MCP-1, ELISA was used to detect the secretion of MCP-1②Adventitial fibroblasts that have been pretreated by some inhibitors of signal transduction pathways for 30 min were incubated by 10-8mol/L urotensin II for 3h and 12h, then the MCP-1 expression were evaluated by RT-PCR and ELISA respectively.
Results: Urotensin II induced monocyte chemoattractant protein-1 expression in a dose-dependent and time-dependent manner, with maximal effect at a concentration of 10-8 mol/l at 3h (in the level of mRNA), 12h (in the level of protein secretion) or 24 h (in the level of protein); These effects were inhibited by the UII receptor antagonist SB710411 (10-6 mol/l), Rho protein kinase inhibitor Y27632 (10-5 mol/l), protein kinase C inhibitor H-7 (10-5 mol/l), mitogen-activated protein kinase inhibitor PD98059 (10-5 mol/l), calcineurin inhibitor Cyclosporine A (10-5 mol/l) and Ca2+ channel blocker nicardipine (10-5 mol/l), The inhibition efficiencies are 64.23%、39.14%、70.76%、68.31%、65.92%和63.47% respectively ( P<0.01).
Conclusion: Urotensin II may stimulate the expression of monocyte chemoattractant protein-1 in rat aortic adventitial fibroblasts through the protein kinase C, mitogen-activated protein kinase, Ca2+ channel, calcineurin and Rho kinase signal transduction pathways, contributing to the vascular inflammation.
目的:观察尾加压素II对血管外膜成纤维细胞(AFs)的MCP-1表达的影响,并进一步研究其细胞内信号转导机制。
方法:①用组织贴块法培养SD大鼠的AFs,用不同浓度的UII(10-10-10-7mol/L)刺激AFs不同时间,然后用逆转录-聚合酶链反应(RT-PCR)及Western印迹法检测MCP-1基因和蛋白的表达,用ELISA法检测MCP-1的胞外分泌情况。②用各细胞内信号转导通路阻断剂预处理AFs 30min,然后用UII (10-8mol/L)刺激AFs 3h和12h,分别从基因水平和蛋白分泌水平观察细胞MCP-1的表达和分泌情况。
结果:UII可呈浓度依赖性地上调MCP-1 mRNA和蛋白的表达,与对照组相比差异均有统计学意义(P值均<0.05),10-8mol/L时达到峰值(P<0.01)。UII的最佳刺激时间点在基因和蛋白水平上分别为3小时和24小时,在蛋白的胞外分泌水平上为12小时。UII的这种刺激MCP-1分泌的作用可以被UII受体阻断剂SB710411、Rho激酶阻断剂Y27632、蛋白激酶C(PKC)阻断剂H-7、促有丝分裂蛋白激酶(MAPK)阻断剂PD98059、钙调神经磷酸酶(CaN)阻断剂Cyclosporine A和钙通道阻断剂Nicardipine所抑制,抑制率分别为64.23%、39.14%、70.76%、68.31%、65.92%和63.47%(P值均<0.01)
结论:UII呈浓度依赖性地促进血管外膜成纤维细胞表达单核细胞趋化蛋白-1,这一作用可通过PKC、MAPK、钙通道、CaN以及Rho信号途径来实现。
Background: Human Urotensin II (UII) is an 11 amino acid cyclic peptide originally isolated from the goby fish. The amino acid sequence of UII is exceptionally conserved across most vertebrate taxa, sharing structural similarity to somatostatin. UII binds to a class of G-protein coupled receptor known as GPR14 or the urotensin receptor (UT). UII and its receptor UT are widely expressed throughout the cardiovascular, pulmonary, central nervous, renal and metabolic systems. UII is generally agreed to be the most potent endogenous vasoconstrictor discovered to date. UII also exerts a wide range of actions in other systems such as proliferation of vascular smooth muscle cells, fibroblasts and cancer cells. It also enhances foam cell formation, chemotaxis of inflammatory cells, inotropic and hypertrophic effects on heart muscle. Many of the major diseases, including cardiovascular disease, such as atherosclerosis, cardiac hypertrophy and heart failure, are widely recognized as inflammatory diseases. Many research support that adventitial fibroblasts may be an early event with a significant role during the development of vascular inflammatory diseases. Monocyte chemoattractant protein-1 (MCP-1) plays a critical role in the development of cardiovascular diseases. But, its mechanisms of urotensin II on the expression of monocyte chemoattractant protein-1 in rat aortic adventitial fibroblasts are discorvered.
Objective: To investigate the effect of urotensin II(UII) on the expression of monocyte chemoattractant protein-1 in rat aortic adventitial fibroblasts, and to study the signal transduction pathways.
Methods:①In cultured adventitial fibroblasts isolated from aorta of adult Sprague-Dawley rats, Growth-arrested adventitial fibroblasts were incubated in serum-free medium with urotensin II (10-10-10-7mol/L) for different lengths time(1h, 3h, 6h, 12h, 24h). Then RT-PCR and Western Blotting was used to detect the expression of MCP-1, ELISA was used to detect the secretion of MCP-1②Adventitial fibroblasts that have been pretreated by some inhibitors of signal transduction pathways for 30 min were incubated by 10-8mol/L urotensin II for 3h and 12h, then the MCP-1 expression were evaluated by RT-PCR and ELISA respectively.
Results: Urotensin II induced monocyte chemoattractant protein-1 expression in a dose-dependent and time-dependent manner, with maximal effect at a concentration of 10-8 mol/l at 3h (in the level of mRNA), 12h (in the level of protein secretion) or 24 h (in the level of protein); These effects were inhibited by the UII receptor antagonist SB710411 (10-6 mol/l), Rho protein kinase inhibitor Y27632 (10-5 mol/l), protein kinase C inhibitor H-7 (10-5 mol/l), mitogen-activated protein kinase inhibitor PD98059 (10-5 mol/l), calcineurin inhibitor Cyclosporine A (10-5 mol/l) and Ca2+ channel blocker nicardipine (10-5 mol/l), The inhibition efficiencies are 64.23%、39.14%、70.76%、68.31%、65.92%和63.47% respectively ( P<0.01).
Conclusion: Urotensin II may stimulate the expression of monocyte chemoattractant protein-1 in rat aortic adventitial fibroblasts through the protein kinase C, mitogen-activated protein kinase, Ca2+ channel, calcineurin and Rho kinase signal transduction pathways, contributing to the vascular inflammation.
引文
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[ 1 ] Coulouarn Y, Lihrmann I, Jegou S, et al. Cloning of the cDNA encoding the urotensin Ⅱprecusor in frog and human reveals intense expression of the urotensinⅡgene in motoneurons of the spinal cord [ J ] . PNAS, 1998, 95: 15803-15808.
[ 2 ] Ames RS, Sarau HM, Chambers JK, et al. Human urotensin-Ⅱis a potent vasoconstrictor and agonist for the orphan receptor GPR14 [ J ] . Nature, 1999, 401: 282-286.
[ 3 ] Maguire JJ, Kuc RE, Davenport AP. Orphan-receptor ligand human urotensinⅡ: receptor localization in human tissues and comparison of vasoconstrictor responses with endothelin-1 [ J ] . Br J Pharmacol, 2000, 131 (3) : 441-446.
[ 4 ] Zhang YG, Li J, Li YG, et al. UrotensinⅡinduces phenotypic differentiation, migration,and collagen synthesis of adventitial fibroblasts from rat aorta [ J ] . J Hypertens, 2008, 26 (6) : 1119-1126.
[ 5 ] Douglas SA, Tayara L, Ohlstein EH. et al. Congestive heart failure and expression of myocardial urotensinⅡ[ J ] . Lancet, 2002, 359 (9322) : 1990-1997.
[ 6 ] Tzanidis A, Hannan RD, Thomas WG, et al. Direct actions of urotensinⅡon the heart: implications for cardiac fibrosis and hypertrophy [ J ] . Circ Res, 2003, 93: 246-253.
[ 7 ] Zhang YG, Li JX, Cao J, et al. Effect of chronic hypoxia on contents of urotensinⅡand its functional receptors in rat myocardium [ J ] . Heart Vessels, 2002, 16 (2) : 64-68.
[ 8 ] Onan D, Pipolo L, Yang E, et al. UrotensinⅡPromotes Hypertrophy of Cardiac Myocytes via Mitogen-Activated Protein Kinases [ J ] . Mol Endocrinol, 2004, 18 (9) : 2344-2354.
[ 9 ]王琼,王汉,沈晓燕.尾加压素Ⅱ诱导培养心肌细胞肥大及对p-p38表达的影响[ J ] .实用医学杂志, 2007, 23 (6) : 804-806.
[ 10 ] Zou YZ, Nagai R, Yamazaki T. UrotensinⅡinduces hypertrophic responses in cultured cardiomyocytes from neonatal rats [ J ] . FEBS Lett, 2001, 508 (1) : 57-60.
[ 11 ] Sousa APF, Silva CB, Pires AL, et al. UrotensinⅡacutely increases myocardial length and distensibility: potential implications for diastolic function and ventricular remodeling [ J ] . Naunyn Schmiedebergs Arch Pharmacol, 2007, 376: 107-115.
[ 12 ] Kompa AR, Thomas WG, See F, et al. Cardiovascular role of urotensinⅡ: effect of chronic infusion in the rat [ J ] . Peptides, 2004, 25 (10) : 1783-1788.
[ 13 ] Johns DG, Ao Z, Naselsky D, et al. Urotensin-Ⅱ-mediated cardiomyocyte hypertrophy: effect of receptor antagonism and role of inflammatory mediators [ J ] . Naunyn Schmiedebergs Arch Pharmacol, 2004, 370 (4) : 238-250.
[ 14 ] Papadopoulos P, Bousette N, Giaid A. Urotensin-Ⅱand cardiovascular remodeling [ J ] . Peptides, 2008, 29 (5) : 764-769.
[ 15 ] Harris GS, Lust RM, DeAntonio JH, et al. PPAR-γexpression in animals subjected to volume overload and chronic UrotensinⅡadministration [ J ] . Peptides, 2008, 29: 795-800.
[ 16 ] Bousette N, Pottinger J, Ramli W, Urotensin-Ⅱreceptor blockade with SB-611812 attenuates cardiac remodeling in experimental ischemic heart disease [ J ] . Peptides, 2006, 27: 2919-2926.
[ 17 ]何艳华,洪介民,郭衡山,等.尾加压素Ⅱ对培养的心脏成纤维细胞增殖和胶原基因表达的影响[ J ] .第一军医大学学报, 2004, 24 (5) : 505-508. He YH, Hong JM, Guo HS, et al. Effects of urotensinⅡon cultured cardiac fibroblast proliferation and collagen type I mRNA expression [ J ] . Di Yi Jun Yi Da Xue Xue Bao, 2004, 24(5): 505-508.
[ 18 ]宋庆刚,吕建庄,杨竞霄.尾加压素Ⅱ促进乳鼠心肌成纤维细胞分泌胶原及增殖的细胞内信号转导机制[ J ] .西安交通大学学报(医学版) , 2007, 28 (2) : 156-160.
[ 19 ] Dai HY, Kang WQ, Wang X, et al. The involvement of transforming growth factor-β1 secretion in UrotensinⅡ-induced collagen synthesis in neonatal cardiac fibroblasts [ J ] . Regulatory Peptides, 2007, 140: 88-93.
[ 20 ] Zhang YG, Li YG, Liu BG, et al. UrotensinⅡaccelerates cardiac fibrosis and hypertrophy of rats induced by isoproterenol [ J ] . Acta Pharmacol Sin, 2007, 28 (1) : 36-43.
[ 21 ] Wang H, Mehta JL, Chen K, et al. Human urotensinⅡmodulates collagen synthesis and the expression of MMP-1 in human endothelial cells [ J ] . J Cardiovasc Pharmacol, 2004, 44 (5) : 577-581.
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[ 1 ] Coulouarn Y, Lihrmann I, Jegou S, et al. Cloning of the cDNA encoding the urotensin Ⅱprecusor in frog and human reveals intense expression of the urotensinⅡgene in motoneurons of the spinal cord [ J ] . PNAS, 1998, 95: 15803-15808.
[ 2 ] Ames RS, Sarau HM, Chambers JK, et al. Human urotensin-Ⅱis a potent vasoconstrictor and agonist for the orphan receptor GPR14 [ J ] . Nature, 1999, 401: 282-286.
[ 3 ] Maguire JJ, Kuc RE, Davenport AP. Orphan-receptor ligand human urotensinⅡ: receptor localization in human tissues and comparison of vasoconstrictor responses with endothelin-1 [ J ] . Br J Pharmacol, 2000, 131 (3) : 441-446.
[ 4 ] Zhang YG, Li J, Li YG, et al. UrotensinⅡinduces phenotypic differentiation, migration,and collagen synthesis of adventitial fibroblasts from rat aorta [ J ] . J Hypertens, 2008, 26 (6) : 1119-1126.
[ 5 ] Douglas SA, Tayara L, Ohlstein EH. et al. Congestive heart failure and expression of myocardial urotensinⅡ[ J ] . Lancet, 2002, 359 (9322) : 1990-1997.
[ 6 ] Tzanidis A, Hannan RD, Thomas WG, et al. Direct actions of urotensinⅡon the heart: implications for cardiac fibrosis and hypertrophy [ J ] . Circ Res, 2003, 93: 246-253.
[ 7 ] Zhang YG, Li JX, Cao J, et al. Effect of chronic hypoxia on contents of urotensinⅡand its functional receptors in rat myocardium [ J ] . Heart Vessels, 2002, 16 (2) : 64-68.
[ 8 ] Onan D, Pipolo L, Yang E, et al. UrotensinⅡPromotes Hypertrophy of Cardiac Myocytes via Mitogen-Activated Protein Kinases [ J ] . Mol Endocrinol, 2004, 18 (9) : 2344-2354.
[ 9 ]王琼,王汉,沈晓燕.尾加压素Ⅱ诱导培养心肌细胞肥大及对p-p38表达的影响[ J ] .实用医学杂志, 2007, 23 (6) : 804-806.
[ 10 ] Zou YZ, Nagai R, Yamazaki T. UrotensinⅡinduces hypertrophic responses in cultured cardiomyocytes from neonatal rats [ J ] . FEBS Lett, 2001, 508 (1) : 57-60.
[ 11 ] Sousa APF, Silva CB, Pires AL, et al. UrotensinⅡacutely increases myocardial length and distensibility: potential implications for diastolic function and ventricular remodeling [ J ] . Naunyn Schmiedebergs Arch Pharmacol, 2007, 376: 107-115.
[ 12 ] Kompa AR, Thomas WG, See F, et al. Cardiovascular role of urotensinⅡ: effect of chronic infusion in the rat [ J ] . Peptides, 2004, 25 (10) : 1783-1788.
[ 13 ] Johns DG, Ao Z, Naselsky D, et al. Urotensin-Ⅱ-mediated cardiomyocyte hypertrophy: effect of receptor antagonism and role of inflammatory mediators [ J ] . Naunyn Schmiedebergs Arch Pharmacol, 2004, 370 (4) : 238-250.
[ 14 ] Papadopoulos P, Bousette N, Giaid A. Urotensin-Ⅱand cardiovascular remodeling [ J ] . Peptides, 2008, 29 (5) : 764-769.
[ 15 ] Harris GS, Lust RM, DeAntonio JH, et al. PPAR-γexpression in animals subjected to volume overload and chronic UrotensinⅡadministration [ J ] . Peptides, 2008, 29: 795-800.
[ 16 ] Bousette N, Pottinger J, Ramli W, Urotensin-Ⅱreceptor blockade with SB-611812 attenuates cardiac remodeling in experimental ischemic heart disease [ J ] . Peptides, 2006, 27: 2919-2926.
[ 17 ]何艳华,洪介民,郭衡山,等.尾加压素Ⅱ对培养的心脏成纤维细胞增殖和胶原基因表达的影响[ J ] .第一军医大学学报, 2004, 24 (5) : 505-508. He YH, Hong JM, Guo HS, et al. Effects of urotensinⅡon cultured cardiac fibroblast proliferation and collagen type I mRNA expression [ J ] . Di Yi Jun Yi Da Xue Xue Bao, 2004, 24(5): 505-508.
[ 18 ]宋庆刚,吕建庄,杨竞霄.尾加压素Ⅱ促进乳鼠心肌成纤维细胞分泌胶原及增殖的细胞内信号转导机制[ J ] .西安交通大学学报(医学版) , 2007, 28 (2) : 156-160.
[ 19 ] Dai HY, Kang WQ, Wang X, et al. The involvement of transforming growth factor-β1 secretion in UrotensinⅡ-induced collagen synthesis in neonatal cardiac fibroblasts [ J ] . Regulatory Peptides, 2007, 140: 88-93.
[ 20 ] Zhang YG, Li YG, Liu BG, et al. UrotensinⅡaccelerates cardiac fibrosis and hypertrophy of rats induced by isoproterenol [ J ] . Acta Pharmacol Sin, 2007, 28 (1) : 36-43.
[ 21 ] Wang H, Mehta JL, Chen K, et al. Human urotensinⅡmodulates collagen synthesis and the expression of MMP-1 in human endothelial cells [ J ] . J Cardiovasc Pharmacol, 2004, 44 (5) : 577-581.
[ 22 ] Borgia F, De Angelis MC, Petretta M, et al. Role of UrotensinⅡsignaling in cardiac remodeling. J Mol Cell Cardiol, 2007, 42(6) Supplement 1: S148.
[ 23 ] Bousette N, Hu F, Ohlstein EH, et al. Urotensin-Ⅱblockade with SB-611812 attenuates cardiac dysfunction in a rat model of coronary artery ligation [ J ] . J Mol Cell Cardiol, 2006, 41 (2) : 285-295.