骨桥蛋白与高血压血管重构的关系及他汀的干预影响
摘要
目的:通过观察肾性高血压大鼠和血压正常大鼠胸主动脉管壁骨桥蛋白(osteopontin,OPN)表达的特点,探讨OPN是否与高血压动脉血管重构有关,并进一步研究阿托伐他汀钙对肾性高血压大鼠胸主动脉OPN表达及重构的影响。
方法:通过两肾一夹方式构建肾性高血压大鼠模型。将21只雄性(Sprague-Dawlay)SD大鼠采用随机数字表法选取7只作为假手术组(n=7),剩余14只大鼠造模成功后采用随机数字表法分为高血压组(n=7)和他汀组(n=7),术后第4周他汀组大鼠开始用阿托伐他汀钙30mg/(kg.d)溶于蒸馏水1ml连续灌胃8周,另两组大鼠同时给予等量蒸馏水灌胃8周。三组大鼠在第4、12周时检测大鼠尾动脉收缩压(systolic blood pressure,SBP),在第12周测定血脂,光镜下观察血管结构变化并计算胸主动脉中膜厚度与内径之比(media thickness/lumen diameter,MT/LD),免疫组织化学法检测OPN的表达水平,荧光定量PCR检测OPN mRNA表达。
结果:第12周时高血压组较假手术组收缩压(systolic blood pressure,SBP)(161±8mmgh vs 112±6mmgh, P<0.05)、中膜厚度/官腔内径( media thickness/lumen diameter ,MT/LD ) (0.067±0.005 vs0.029±0.005, P<0.05)、OPN(0.24±0.07 vs 0.10±0.06, P<0.05)及OPN mRNA(0.1435±0.0434 vs 0.0554±0.0235, P<0.05)表达显著升高,总胆固醇(total cholesterol,TC)、低密度脂蛋白胆固醇(low density lipoprotein cholesterol,LDL-c)及高密度脂蛋白胆固醇(high density lipoprotein cholesterol,HDL-c)水平显著降低(P<0.05)。他汀组较高血压组MT/LD(0.036±0.005 vs 0.067±0.005, P<0.05)、OPN(0.18±0.09 vs 0.24±0.07, P<0.05)及OPN mRNA(0.0994±0.0293 vs 0.1435±0.0434)表达显著降低(P<0.05),HDL-c水平明显升高(P<0.05),而TC、LDL-c水平明显降低(P<0.05)。
结论:(1)高血压组大鼠胸主动脉重构明显,OPN及OPN mRNA表达均显著高于假手术组大鼠,这提示我们高血压状态可导致动脉血管OPN表达增加,且OPN的过度表达可能与高血压动脉血管重构有关;(2)他汀组大鼠胸主动脉重构较高血压组大鼠得到明显改善,且他汀组大鼠胸主动脉OPN及OPN mRNA表达也显著低于高血压组大鼠,阿托伐他汀钙可能通过抑制高血压动脉血管OPN的过度表达而改善血管重构。
Objective:To investigate the differences on osteopontin expression (OPN) of thoracic aorta between renovascular hypertensic rats and normol rats, then discuss the relation of OPN and vascular remodeling in hypertension, and reaserch the influence of the atorvastain calcium on the expression of OPN and vascular renmodeling in renovascular hypertensic rats in the end.
Methods: The 2-kindey,1-clip hypertensive rats were prepared with male (Sprague-Dawlay)SD rat. Twenty-one rats were randomized into sham group(n=7), hypertension group(n=7) and statins group(n=7). Statins group was treated with atorvastatin calcium 30mg/(kg.d) four weeks after model construction and lasted 8 consecutive weeks, given through lavage. All rats were evaluated caudal systolic blood pressure(SBP) and blood lipid, microscopic changes in vascular structure and ratio of intima media thickness to lumen diameter(MT/LD) of thoracic aorta. Expressions of OPN were assessed with immunohistochemical staining, expressions of OPN mRNA with Real-time quantitative PCR.
Results: Compared with sham group, hypertensive group showed significant increase in SBP(161±8mmgh vs 112±6mmgh, P<0.05)、MT/LD(0.067±0.005 vs 0.029±0.005, P<0.05) and the expression of OPN(0.24±0.07 vs 0.10±0.06, P<0.05) and OPN mRNA(0.1435±0.0434 vs 0.0554±0.0235, P<0.05), and significant decrease in TC、LDL-c and HDL-c level(P<0.05). As compared with hypertensive group, MT/LD(0.036±0.005 vs 0.067±0.005, P<0.05) and the expression of OPN(0.18±0.09 vs 0.24±0.07, P<0.05) and OPN mRNA(0.0994±0.0293 vs 0.1435±0.0434) of statins group were significantly decreased, HDL-c level significantly increased(P<0.05) , TC、LDL-c level significantly decreased(P<0.05).
Conclusions: (1) The significantly increased OPN expression of the thoracic aorta may be related to the development of hypertensive vascular remodeling.(2)Atorvastatin calcium was shown to improve the development of vascular remodeling in rats, possibly associated with decreased expression of OPN.
方法:通过两肾一夹方式构建肾性高血压大鼠模型。将21只雄性(Sprague-Dawlay)SD大鼠采用随机数字表法选取7只作为假手术组(n=7),剩余14只大鼠造模成功后采用随机数字表法分为高血压组(n=7)和他汀组(n=7),术后第4周他汀组大鼠开始用阿托伐他汀钙30mg/(kg.d)溶于蒸馏水1ml连续灌胃8周,另两组大鼠同时给予等量蒸馏水灌胃8周。三组大鼠在第4、12周时检测大鼠尾动脉收缩压(systolic blood pressure,SBP),在第12周测定血脂,光镜下观察血管结构变化并计算胸主动脉中膜厚度与内径之比(media thickness/lumen diameter,MT/LD),免疫组织化学法检测OPN的表达水平,荧光定量PCR检测OPN mRNA表达。
结果:第12周时高血压组较假手术组收缩压(systolic blood pressure,SBP)(161±8mmgh vs 112±6mmgh, P<0.05)、中膜厚度/官腔内径( media thickness/lumen diameter ,MT/LD ) (0.067±0.005 vs0.029±0.005, P<0.05)、OPN(0.24±0.07 vs 0.10±0.06, P<0.05)及OPN mRNA(0.1435±0.0434 vs 0.0554±0.0235, P<0.05)表达显著升高,总胆固醇(total cholesterol,TC)、低密度脂蛋白胆固醇(low density lipoprotein cholesterol,LDL-c)及高密度脂蛋白胆固醇(high density lipoprotein cholesterol,HDL-c)水平显著降低(P<0.05)。他汀组较高血压组MT/LD(0.036±0.005 vs 0.067±0.005, P<0.05)、OPN(0.18±0.09 vs 0.24±0.07, P<0.05)及OPN mRNA(0.0994±0.0293 vs 0.1435±0.0434)表达显著降低(P<0.05),HDL-c水平明显升高(P<0.05),而TC、LDL-c水平明显降低(P<0.05)。
结论:(1)高血压组大鼠胸主动脉重构明显,OPN及OPN mRNA表达均显著高于假手术组大鼠,这提示我们高血压状态可导致动脉血管OPN表达增加,且OPN的过度表达可能与高血压动脉血管重构有关;(2)他汀组大鼠胸主动脉重构较高血压组大鼠得到明显改善,且他汀组大鼠胸主动脉OPN及OPN mRNA表达也显著低于高血压组大鼠,阿托伐他汀钙可能通过抑制高血压动脉血管OPN的过度表达而改善血管重构。
Objective:To investigate the differences on osteopontin expression (OPN) of thoracic aorta between renovascular hypertensic rats and normol rats, then discuss the relation of OPN and vascular remodeling in hypertension, and reaserch the influence of the atorvastain calcium on the expression of OPN and vascular renmodeling in renovascular hypertensic rats in the end.
Methods: The 2-kindey,1-clip hypertensive rats were prepared with male (Sprague-Dawlay)SD rat. Twenty-one rats were randomized into sham group(n=7), hypertension group(n=7) and statins group(n=7). Statins group was treated with atorvastatin calcium 30mg/(kg.d) four weeks after model construction and lasted 8 consecutive weeks, given through lavage. All rats were evaluated caudal systolic blood pressure(SBP) and blood lipid, microscopic changes in vascular structure and ratio of intima media thickness to lumen diameter(MT/LD) of thoracic aorta. Expressions of OPN were assessed with immunohistochemical staining, expressions of OPN mRNA with Real-time quantitative PCR.
Results: Compared with sham group, hypertensive group showed significant increase in SBP(161±8mmgh vs 112±6mmgh, P<0.05)、MT/LD(0.067±0.005 vs 0.029±0.005, P<0.05) and the expression of OPN(0.24±0.07 vs 0.10±0.06, P<0.05) and OPN mRNA(0.1435±0.0434 vs 0.0554±0.0235, P<0.05), and significant decrease in TC、LDL-c and HDL-c level(P<0.05). As compared with hypertensive group, MT/LD(0.036±0.005 vs 0.067±0.005, P<0.05) and the expression of OPN(0.18±0.09 vs 0.24±0.07, P<0.05) and OPN mRNA(0.0994±0.0293 vs 0.1435±0.0434) of statins group were significantly decreased, HDL-c level significantly increased(P<0.05) , TC、LDL-c level significantly decreased(P<0.05).
Conclusions: (1) The significantly increased OPN expression of the thoracic aorta may be related to the development of hypertensive vascular remodeling.(2)Atorvastatin calcium was shown to improve the development of vascular remodeling in rats, possibly associated with decreased expression of OPN.
引文
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[1] Han M, Wen JK, Zheng B, etal. Blockade of integrin beta3-FAK signaling pathway activated by osteopontin inhibits neointimal formation after balloon injury[J]. Cardiovasc Pathol. 2007, 16(5): 283-290.
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[28]刘智敏,韩梅,温进坤。细胞外基质促血管平滑肌细胞迁移及β3整合素和粘着斑激酶表达[J]。中国病理生理杂志,2003,19(2):163-6。
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[31] Kalyanasundaram A, Elmore JR, Manazer JR, etal. Simvastatin suppresses experimental aortic aneurysm expansion[J]. J Vasc Surg. 2006, 43(1):117-24.
[32] Chironi G, Simon A, Gariepy J, etal. Differential associations of statin and fibrate treatment with carotid arterial remodeling[J]. Am J Hypertens. 2005, 18(11): 1476-81.
[33]刘敏,吴义超,张炜等。阿托伐他汀对大鼠移植肾骨桥蛋白表达的影响[J]。中国组织工程研究与临床康复。2007,11(1):605-9。
[34]刘超,江志奎,程筱雯等。阿伐他汀对高胆固醇血症ApoE基因敲除小鼠肝脏骨桥蛋白表达的影响[J]。安徽医科大学学报。2008,43(6):670-73。
[35] Renault MA, Jalvy S, Potier M, etal. UTP induces osteopontin expression through acoordinate action of NFkappaB, activator protein-1, and upstream stimulatory factor in arterial smooth muscle cells[J]. J Biol Chem. 2005, 280(4): 2708-13.
[36] Ortego M, Bustos C, Hernández-Presa MA, etal. Atorvastatin reduces NF-kappaB activation and chemokine expression in vascular smooth muscle cells and mononuclear cells[J]. Atherosclerosis. 1999, 147(2): 253-61.
[37] Musial J, Undas A, Gajewski P, etal. Anti-inflammatory effects of simvastatin in subjects with hypercholesterolemia[J]. Int J Cardiol, 2001, 77(2-3): 247-53.
[2] Giachelli CM, Bae N, Almeida M, eta1. Osteopontin is elevated during neointima formation in rat arteries and is a novel component of human atherosclerotic plaques[J]. J Clin Invest. 1993, 92 (4):1686-96.
[3] Iizuka K, Murakami T, Kawaguchi H. Pure atmospheric pressure promotes an expression of osteopontin in human aortic smooth muscle cells. Biochem Biophys Res Commun. 2001,283 (2):493-8.Hirsch AT. Vascular disease, hypertension, and prevention:“from endothelium to clinic events”[J]. J Am Coll Cardiol. 2003, 42(2): 377-9.
[4] Han M, Wen JK, Zheng B, etal. Blockade of integrin beta3-FAK signaling pathway activated by osteopontin inhibits neointimal formation after balloon injury[J]. Cardiovasc Pathol. 2007, 16(5): 283-290.
[5] Bidder M, Shao JS, Charlton-Kachigian N, etal. Osteopontin transcription in aortic vascular smooth muscle cells is controled by glucose-regulated upstream stimulatory factor and activator protein-1 activities[J]. J Biol Chem. 2002(46), 277: 44485-96.
[6] Vogt F, Zemecke A, Beckner M, eta1. Blockade of anglo-associated migratory cell protein inhibits smooth muscle cell migration and neointima formation in accelerated atherosclerosis[J]. J Am Coil Cardiol, 2008, 52(4): 302-311.
[7] Kalyanasundaram A, Elmore JR, Manazer JR, etal. Simvastatin suppresses experimental aortic aneurysm expansion[J]. J Vasc Surg. 2006, 43(1): 117-24.
[8] Chironi G, Simon A, Gariepy J, etal. Differential associations of statin and fibrate treatment with carotid arterial remodeling[J]. Am J Hypertens. 2005, 18(11): 1476-81.
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