坎地沙坦西酯对动脉粥样硬化大鼠MCP-1、CRP的影响
|
摘要
目的：通过建立动脉粥样硬化的大鼠模型,观察坎地沙坦西酯对大鼠主动脉粥样硬化的作用,及对MCP-1、CRP含量的影响,从而观察坎地沙坦西酯的抗炎作用。
方法：选取30只健康的雄性Wistar大鼠,随机分为3组,正常对照组(NC)、高脂对照组(HC)、坎地沙坦西酯组(HC+C),分别饲养8周。①血脂测定：分别于实验前及8周末采血,用化学法测定血清血脂水平；②血清hs-CRP测定：分别于实验前及8周末取大鼠血清,用酶联免疫吸附试验(ELISA法)检测大鼠血清中的hs-CRP含量变化；③大鼠主动脉病理形态观察：饲养8周末,大鼠麻醉后迅速开胸,分离胸主动脉,固定、切片、脱水及HE染色,光镜下观察主动脉形态并拍照；④胸主动脉MCP-1蛋白的表达：分离的主动脉进行石蜡固定、切片、脱水,免疫组织化学法染色,光镜下观察主动脉MCP-1蛋白的表达情况并照相,用病理图像分析系统测定平均灰度值,并进行比较。
结果：①实验前各组大鼠血脂水平相似(P>0.05)；8周末,HC组及HC+C组大鼠TG、TC、LDL-C较NC组明显升高(P<0.01),HC组与HC+C组相比较,差异不大,无统计学意义(P>0.05)。②实验前各实验组大鼠hs-CRP含量相似,无显著性差异(P>0.05)。8周末,HC组大鼠hs-CRP含量较NC组明显升高(P<0.01), HC+C组大鼠,显著降低hs-CRP含量(P<0.01)。③HC组大鼠主动脉内膜增厚,中膜可见平滑肌纤维排列紊乱,外膜炎症细胞浸润,HC+C组介于NC组及HC组之间,内膜轻度增厚、外膜少量炎细胞浸润。④各实验组MCP-1蛋白表达阳性表现呈棕黄色颗粒,位于胞膜及胞浆内,主要见于新生内膜,中膜亦有表达。NC组及HC+C组平均灰度值(分别为156.94±8.158、130.98±5.941)明显高于HC组(123.74±5.616)(P<0.01)。
结论：①坎地沙坦西酯不影响AS大鼠的血脂水平；②坎地沙坦西酯有抗炎作用,使hs-CRP及MCP-1水平降低；③坎地沙坦西酯可能延缓AS的进程。
Objective:This study sought to investigate the effect of candesartan on the expression of monocyte chemoattractant protein-1, high-sensitivity C-reactive protein and so on, in order to examining the effect of candesartan on the formation of atherosclerosis.
Method:There is thirty male wistar rats that were randomly divided into three groups, each group had ten:normal control group (NC)、high-cholesterol control group (HC)、high-cholesterol+candesartan group (HC+C),the rats were fed for eight weeks.①The concentrations of lipid in plasma were measured by chemical method at 0-week、8-week respectively, compared with the control group.②Collected the blood at 0-week and 8-week respectively, detected with enzyme-linked immunosorbent assay(ELISA), compared with each other.③The rats for 8-week feeding,anesthesia, rapid thoracotomy, aortic isolated, fixed, sliced, dehydrated, and HE staining, observed artery intima-media thickness under light microscope, and photoed.④Detected expression of MCP-1 by immunohistochemistry, calculated the average gray value, and compared.
Results:①Candesartan cilexetil on the levels of lipid in atherosclerotic rats:before experiment, the lipid levels in plasma were similar among each groups, there was no significant difFerence(P>0.05);At the end of 8 weeks, concentrations of lipid in HC and HC+C group were significantly higher than that in NC group(P<0.01),there was no difference between HC and HC +C group(P>0.05).②Observed changes in hs-CRP in each group:before the experiment the levels of hs-CRP were similar among each groups, there was no significant difference(P>0.05). After 8 weeks, the concentrations of hs-CRP in HC group were significantly higher than that in HC+C group (P<0.01).③The effect of candesartan on arterial intima-media thickness:the arterial intima-media in HC group was thicker than the others, muscle fibers can be seen in the disordered membrane, inflammatory cell infiltrated outer membrane. In HC+C group than in HC group with mild intimal thickening, adventitial small infiltration of inflammatory cells.④The effect of candesartan on expression of MCP-1:MCP-1 protein expression showed a positive brown particles in the membrane and the cytoplasm, mainly seen in the neointima, also expressed in the membrane. The average gray value in NC and HC+C group(respectively, 156.94±8.158、130.98±5.941) was significantly higher than that in HC group(123.74±5.616) (P<0.01)
Conclusion:①Candesartan can't reduce the lipid levels.②Candesartan can lower the expression of MCP-1 and hs-CRP, so candesartan cilexetil have anti-inflammatory effects.③Candesartan cilexetil maybe delay the process of atherosclerosis.
方法：选取30只健康的雄性Wistar大鼠,随机分为3组,正常对照组(NC)、高脂对照组(HC)、坎地沙坦西酯组(HC+C),分别饲养8周。①血脂测定：分别于实验前及8周末采血,用化学法测定血清血脂水平；②血清hs-CRP测定：分别于实验前及8周末取大鼠血清,用酶联免疫吸附试验(ELISA法)检测大鼠血清中的hs-CRP含量变化；③大鼠主动脉病理形态观察：饲养8周末,大鼠麻醉后迅速开胸,分离胸主动脉,固定、切片、脱水及HE染色,光镜下观察主动脉形态并拍照；④胸主动脉MCP-1蛋白的表达：分离的主动脉进行石蜡固定、切片、脱水,免疫组织化学法染色,光镜下观察主动脉MCP-1蛋白的表达情况并照相,用病理图像分析系统测定平均灰度值,并进行比较。
结果：①实验前各组大鼠血脂水平相似(P>0.05)；8周末,HC组及HC+C组大鼠TG、TC、LDL-C较NC组明显升高(P<0.01),HC组与HC+C组相比较,差异不大,无统计学意义(P>0.05)。②实验前各实验组大鼠hs-CRP含量相似,无显著性差异(P>0.05)。8周末,HC组大鼠hs-CRP含量较NC组明显升高(P<0.01), HC+C组大鼠,显著降低hs-CRP含量(P<0.01)。③HC组大鼠主动脉内膜增厚,中膜可见平滑肌纤维排列紊乱,外膜炎症细胞浸润,HC+C组介于NC组及HC组之间,内膜轻度增厚、外膜少量炎细胞浸润。④各实验组MCP-1蛋白表达阳性表现呈棕黄色颗粒,位于胞膜及胞浆内,主要见于新生内膜,中膜亦有表达。NC组及HC+C组平均灰度值(分别为156.94±8.158、130.98±5.941)明显高于HC组(123.74±5.616)(P<0.01)。
结论：①坎地沙坦西酯不影响AS大鼠的血脂水平；②坎地沙坦西酯有抗炎作用,使hs-CRP及MCP-1水平降低；③坎地沙坦西酯可能延缓AS的进程。
Objective:This study sought to investigate the effect of candesartan on the expression of monocyte chemoattractant protein-1, high-sensitivity C-reactive protein and so on, in order to examining the effect of candesartan on the formation of atherosclerosis.
Method:There is thirty male wistar rats that were randomly divided into three groups, each group had ten:normal control group (NC)、high-cholesterol control group (HC)、high-cholesterol+candesartan group (HC+C),the rats were fed for eight weeks.①The concentrations of lipid in plasma were measured by chemical method at 0-week、8-week respectively, compared with the control group.②Collected the blood at 0-week and 8-week respectively, detected with enzyme-linked immunosorbent assay(ELISA), compared with each other.③The rats for 8-week feeding,anesthesia, rapid thoracotomy, aortic isolated, fixed, sliced, dehydrated, and HE staining, observed artery intima-media thickness under light microscope, and photoed.④Detected expression of MCP-1 by immunohistochemistry, calculated the average gray value, and compared.
Results:①Candesartan cilexetil on the levels of lipid in atherosclerotic rats:before experiment, the lipid levels in plasma were similar among each groups, there was no significant difFerence(P>0.05);At the end of 8 weeks, concentrations of lipid in HC and HC+C group were significantly higher than that in NC group(P<0.01),there was no difference between HC and HC +C group(P>0.05).②Observed changes in hs-CRP in each group:before the experiment the levels of hs-CRP were similar among each groups, there was no significant difference(P>0.05). After 8 weeks, the concentrations of hs-CRP in HC group were significantly higher than that in HC+C group (P<0.01).③The effect of candesartan on arterial intima-media thickness:the arterial intima-media in HC group was thicker than the others, muscle fibers can be seen in the disordered membrane, inflammatory cell infiltrated outer membrane. In HC+C group than in HC group with mild intimal thickening, adventitial small infiltration of inflammatory cells.④The effect of candesartan on expression of MCP-1:MCP-1 protein expression showed a positive brown particles in the membrane and the cytoplasm, mainly seen in the neointima, also expressed in the membrane. The average gray value in NC and HC+C group(respectively, 156.94±8.158、130.98±5.941) was significantly higher than that in HC group(123.74±5.616) (P<0.01)
Conclusion:①Candesartan can't reduce the lipid levels.②Candesartan can lower the expression of MCP-1 and hs-CRP, so candesartan cilexetil have anti-inflammatory effects.③Candesartan cilexetil maybe delay the process of atherosclerosis.
引文
[1]Munzel T, Sinning C, Post F, et al. Pathophysiology, diagnosis and prognostic implications of endothelial dysfunction. Ann Med.2008,40(3):180-196.
[2]Sakamoto T, Ishibashi T, Sakamoto N, et al. Endogenous NO blockade enhances tissue factor expression via increased Ca2+ influx through MCP-1 in endothelial cells by monocyte adhesion [J]. Arterioscler Thromb Vasc Biol,2005,25(9):2005-2011.
[3]Park SY, Lee JH, Kim YK, et al. Cilostazol prevents remnant lipoprotein particle-induced monocyte adhesion to endothelial cells by suppression of adhesion molecules and monocyte chemoattractant protein-1 expression via lectin-like receptor for oxidized low-density lipoprotein receptor activation [J]. Pharmacol Exp Ther,2005,312(3):1241-1248.
[4]Coll B,Alonso-Villaverde C,Joven J.Monocyte chemoattractant protein-1 and atherosclero-sis:is there room for an additional biomarker? Clin Chim Acta,2007,383:21-29.
[5]Provatoriv SI, Aref,eva TI, Kukhtina NB, et al. Markers of inflammation-monocyte chemoattractant protein-1 (MCP-1) and C-reactive protein--in blood of patients with unstable angina pectoris and stable effort angina [J]. Ter Arkh,2006,78 (6):66-69.
[6]Feng XP, Dong WB, Chen XS. Monocyte chemotactic protein-1 expression in coronary atherosclerosis plaque of sudden coronary death patients [J]. Zhanghua Xin Xue Guan Bing Za Zhi,2006,34(7):589-601.
[7]Jialal I,Devaraj S,Venugopal SK.C-reactive protein:risk marker or mediator in athero-thrombosis? Hypertension 2004,44(1):6-11.
[8]Fichtlscherer S,Rosenberger G,Walter DH,et al.Elevated C-reactive protein levels and impaired endothelial vasoreactivity in patients with coronary artery disease. Circulation,2000, 102(9):1000-1006.
[9]Cleland SJ,Sattar N,Petrie JR,et al. Endothelial dysfunction as a possible link between C-reactive protein levels and cardiovascular disease. Clin Sci (Lond),2000,98(5):531-535.
[10]Nabata A, Kuroki M, Ueba H, et al. C-reactive protein induces endothelial cell apoptosis and matrix metalloproteinase-9 production in human mononuclear cells:implications for the destabilization of atherosclerotic plaque. Atherosclerosis,2008,196(1):129-135.
[11]Wang CH, Li SH, Weisel RD, et al. C-reactive protein upregulates angiotensin type 1 receptors in vascular smooth muscle. Circulation,2003,107(13):1783-1790.
[12]Vincenzo Pasceri,Jed Chang,James T. Willerson,et al.Modulation of C-Reactive Protein-Mediated Monocyte Chemoattractant Protein-1 Induction in Human Endothelial Cells by Anti-Atherosclerosis Drugs. Circulation,2001,103:2531-2534.
[13]Ki Hoon Han,Kyung-Hee Hong,Jae-Hyeong Park,et al. C-Reactive Protein Promotes Monocyte Chemoattractant Protein-1-Mediated Chemotaxis Through Upregulating CC Chemokine Receptor 2 Expression in Human Monocytes. Circulation,2004,109:2566-2571.
[14]Koh KK, Ahn J Y, Han SH,et al. Pleiot ropic effect s of angiotensin Ⅱ receptor blocker in hypertensive patients [J]. J Am Coll Cardiol,2003,42 (5):905-910.
[15]杨晓云.抗动脉粥样硬化药对家兔动脉粥样硬化血管壁NF-Kb-DNA结合活性及炎性因子影响的实验研究： [博士学位论文].武汉：华中科技大学,2006年.
[16]Pfeffer MA, McMurray JJ, Velazquez EJ, et al. Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. N Engl J Med, 2003,349(20):1893-1906.
[17]The_ONTARGET_Investigators. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med,2008,358:1547-1559.
[18]Byron J. Hoogwerf. Renin-Angiotensin System Blockade and Cardio-vascular an Renal Protection.Am J Cardiol,2010,105:30-35.
[19]Hiroki Ikeda, Jun Minamikawa, Yoshio Nakamura. Comparison of effects of amlodipine and angiotensin receptor blockers on the intima-media thickness of carotid arterial wall (AAA study:Amlodipine vs. ARB in atherosclerosis study), [J]. Diabetes Research and Clinical Practice,2009,83:50-53.
[20]Erling Falk.Pathogenesis of Atherosclerosis, J Am Coll Cardiol,2006,47:7-12.
[21]Munzel T, Sinning C, Post F,et al. Pathophysiology, diagnosis and prognostic implications of endothelial dysfunction. Ann Med,2008,40(3):180-196.
[22]Dzau VJ. Theodore Cooper lecture:tissue angiotensin and pathobiology of vascular disease: a unifying hypothesis. Hypertension,2001,37:1047-1052.
[23]Fukuda D, Sata M, Ishizaka N, et al. Critical role of bone marrow angiotensin Ⅱ type 1 receptor in the pathogenesis of atherosclerosis in apolipoprotein E deficient mice. Arterioscler Thromb Vasc Biol,2008,28:90-96.
[24]Chrysant SG, Chrysant GS. Clinical experience with angiotensin receptor blockers with particular reference to valsartan. Clin Hypertens (Greenwich),2004,6:445-451.
[25]Libby P. Inflammation in atherosclerosis. Nature,2002,420:868-74.
[26]Pueyo ME,Gonzalez W,Nicoletli A,et al.Angiotensin Ⅱ stimulates endothelial vascular cell adhesion molecular-1 via nuclear factor-kB activtion induced by intracellular oxidative stress[J]. Arterioscler Thromb Vasc Biol,2000,20:645.
[27]Li Jing,Hirose N,Kawamura M,et al.Antiatherogenic effect of angiotensin converting enzyme inhibiter and angiotensin Ⅱ receptor antagonist in the cholesterol fed rabbits[J]. Atherosclerosis,1999,143:315.
[28]Qiying Xie, Ming Sun, Tian-lun Yang,et al. Losartan reduces monocyte chemoattractant protein-1 expression in aortic tissues of 2K1C hypertensive rats. International Journal of Cardiology,2006,110:60-66.
[29]董波,高顺宗,黄定九,等.氯沙坦对动脉粥样硬化兔的MCP-1及基因表达的实验研究.上海免疫学杂志,2002,22(4)；260-262.
[30]Willerson JT,Ridkre PM. Inflammation as a cardiovascular risk factor. Circulation,2004, 109:2-10.
[31]王明毅.替米沙坦对高血压患者血清C反应蛋白的影响.药物与临床.2010,17(2)：59-60.
[32]付军,白晶,冷吉燕,等.替米沙坦对原发性高血压患者左室肥厚及C反应蛋白的干预作用.中国老年学杂志.2008,28：1916-1918.
[33]仝其广编译.内皮下脂蛋白滞留——动脉粥样硬化的始动过程.心血管病学进展,2008,29(1)： 38-40.
[34]Kumiko Arishiro,Masaaki Hoshiga.Angiotensin Receptor-1 Blocker Inhibits Atherosclerotic Changes and Endothelial Disruption of the Aortic Valve in Hypercholesterolemic Rabbits, J Am Coll Cardiol,2007,49:1482-1489.
[35]Ridker PM, Danielson E, Fonseca FA, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl,J Med,2008,359:2195-2207.
[I]Cipollone F,Marini M,Fazia M,et al.Elevated circulating levels of monocytes chemo-attractant protein 1 in patients with restenosis after coronary angioplasty [J]. Arterioscler Thromb Vasc Biol,2001,21(3):327-334.
[2]Harrington JR. The role of MCP-1 in atherosclerosis [J]. Stem Cells,2000,18(1):65-66.
[3]Frisinghelli A, Mafrici A. Regression or reduction in progression of athero-sclerosis, and avoidance of coronary events, with lovastatin in patients with or at high risk of cardiovascular disease:a review. Clin Drug Investig,2007,27:591-604.
[4]Coll B, Alonso-Villaverde C, Joven J. Monocyte chemoattractant protein-1 and atherosclerosis:is there room for an additional biomarker? Clin Chim Acta,2007,383:21-29.
[5]Kusano KF, Nakamura K, Kusano H, et al. Significance of the level of monocyte chemoattractant protein-1 in human atherosclerosis. Circ J,2004,68:671-676.
[6]Harvey EJ, Li N, Ramji DP. Critical role for casein kinase 2 and phosphoinositide-3-kinase in the interferon-gamma-induced expression of monocyte chemoattractant protein-1 and other key genes implicated in atherosclerosis. Arterioscler Thromb Vasc Biol,2007,27:806-812.
[7]Sakamoto T,Ishibashi T,Sakamoto-N,et al.Endogenous NO blockade enhances tissue factor expression via increased Ca2+ influx through MCP-1 in endothelial cells by monocyte adhesion [J]. Arterioscler Thromb Vasc Biol,2005,25(9):2005-2011.
[8]Park SY, Lee JH, Kim YK, et al. Cilostazol prevents remnant lipoprotein particle-induced monocyte adhesion to endothelial cells by suppression of adhesion molecules and monocyte chemoattractant protein-1 expression via lectin-like receptor for oxidized low-density lipoprotein receptor activation [J]. Pharmacol Exp Ther,2005,312(3):1241-1248.
[9]王文勇,唐红卫,张志培.CD34和血管内皮生长因子在人甲状腺癌组织中的表达及微血管密度的病理意义[J].第四军医大学学报(新),2005,25(15).
[10]Weihua Ni,Kensuke Egashira,Shiro Kitamoto,et al. New Anti-Monocyte Chemoattractant Protein-1 GeneTherapy Attenuates Atherosclerosis in Apolipoprotein E-Knockout Mice [J] Circulation,2001,103:2096-2101.
[11]Shujiro Inoue, Kensuke Egashira, Weihua Ni. Anti-Monocyte Chemoattractant Protein-1 Gene Therapy Limits Progression and Destabilization of Established Atherosclerosis in Apolipoprotein E-Knockout Mice. Circulation,2002,106:2700-2706.
[12]Roque M, Kim WJ, GazdoinM, et al. CCR2 deficiency decreases intimal hyperplasia after arterial injury [J].Arterioscler Thromb Vasc Biol,2002,22:554-559.
[13]Bursill CA, Channon KM, Greaves DR. The role of chemokines in athersclerosis:recent evidence from experimental models and population genetics [J]. Curr Opin Lipidol,2004,15 (2):145-149.
[14]Mazzone, S De Servi, IM azzucchelli, et al. Increased concentrations of inflammatory mediators in unstable angina:correlation with serum troponin T [J]. Heart,2001,85:571.
[15]Kervinen H, M anttari M, Kaatinen M, et al. Prognostic usefulness of plasma monocyte macrophage and T lymphocyte 2 activation markers in patients with acute coronary syndromes [J]. Am J Cardiol,2004,94 (8):993-996.
[16]Liuzzo,goronzy JJ,Yang H, et al. monoclonal T-cell proliferation and plaque instability in acute coronary syndromes [J].Circulation,2000,101:2883-2888.
[17]Provatoriv SI,Aref,eva TI,Kukhtina NB,et al.Markers of inflammation-monocyte chemoattractant protein-1 (MCP-1) and C-reactive protein—in blood of patients with unstable angina pectoris and stable effort angina [J]. Ter Arkh,2006,78 (6):66-69.
[18]Park HJ, Chang K, Park CS,et al. Coronary collaterals:The role of MCP-1 during the early phase of acute myocardial infarction[J]. Int J Cardiol,2007.
[19]Feng XP, Dong WB, Chen XS. Monocyte chemotactic protein-1 expression in coronary atherosclerosis plaque of sudden coronary death patients [J]. Zhanghua Xin Xue Guan Bing Za Zhi,2006,34(7):589-601.
[20]吕春美,彭子敬,田国平.单核细胞趋化蛋白-1对不稳定型心绞痛患者近期心血管事件的预测价值[J],医学临床研究,2008,25(4)：664-666.
[21]Frauke S,Czepluch,Bernhard Zweigle, et al. Chemotaxis analysis of circulating mono-cytes in patients with a recent acute coronary syndrome. Atherosclerosis,2009,204:304-308.
[22]Madej A,Okopien B,Kowalski J, et al. Plasma concentra-tions of adhesion molecules and chemokines in patients with essential hypertension [J]. Pharmacol Rep,2005,57 (6):878-881.
[23]Parissis J T,Korovesis S,Giazitzoglou E,et al. Plasma profiles of peripheral monocyte related inflammatory markers in patients with arterial hypertension. Correlations with plasma endothelin-1 [J]. Int J Cardiol,2002,83:13-21.
[24]Prasad A,Koh KK,Schenke WH,et al.Role of angiotensin Ⅱ type 1 receptor in the regulation of cellular adhesion molecules in atherosclerosis[J]. Am Heart J,2001,142:248-253.
[25]谢启应 孙明 杨天伦,等.高血压病患者血清单核细胞趋化因子-1的变化及其与血管紧张素Ⅱ的关系[J],中国现代医学杂志,2003,13(23)：111-112.
[26]Rodriguez-Iturbe B,Ferrebuz A,Vanegas V,et al.Early and sustained inhibition of nuclear factor-kappa B prevents hypertension in spontaneously hypertensive rats [J]. J Pharmacol Exp Ther,2005,315(1):51-57.
[27]Tonnessen T,Florholmen G,Henriksen UL,et al. Cardiopulmonary alterations in mRNA expression for interleukin-lbeta, the interleukin-6 superfamily and CXC-chemokines during development of postischaemic heart failure in the rat [J]. Clin Physiol Funct Imaging,2003,23 (5)：263-268.
[28]刘芳,辛志强,丁春平,等.CHF血清单核细胞趋化蛋白-1的变化及其与脂质过氧化的关系[J],中国临床实用医学,2007,10(1)：21-23.
[29]王斌,赵连友,郑强荪,等.高血压心肌纤维化的发病机制：成纤维细胞在血管紧张素Ⅱ刺激下单核细胞趋化蛋白-1的表达状况.中国临床康复,2004,8(9)：1683-1685.
[30]Schillinger M,Exner M,Amighi J,et al. Joint effects of C-reactive protein and glycated hemoglobin in predicting future cardiovascular events in patients with advanced atherosclerosis. Circulation,2003,108:2323-2328.
[31]Ridker PM,Rifai N,Rose L,et al.Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events. N Engl J Med,2002, 347:1557-1565.
[32]Ridker PM. C-reactive protein:eighty years from discovery to emergence as a major risk marker for cardiovascular disease. Clin Chem,2009,55:209-215.
[33]Hingorani AD,Shah T,Casas JP,et al. C-reactive protein and coronary heart disease: predictive test or therapeutic target? Clin Chem,2009,55:239-255.
[34]Danesh J,Wheeler JG,Hirschfield GM,et al. C-reactive protein and other circulating markers of inflammation in the prediction of coronary heart disease. N Engl J Med,2004,350: 1387-1397.
[35]尹浩晔,马梅,周馨.高敏C反应蛋白、血浆脑钠肽与急性关脉综合症严重程度的关系.山东医药,2009,49(41)：48-49.
[36]Reza Alizadeh Dehnavi,Albert de Roos,Ton J. Rabelink, Elevated CRP levels are associated with increased carotid atherosclerosis independent of visceral obesity. Atherosclerosis,2008,200: 417-423.
[37]Jialal I,Devaraj S,Venugopal SK.C-reactive protein:risk marker or mediator in athero-thrombosis? Hypertension,2004,44(1):6-11.
[38]B.G. Nordestgaard, J. Zacho. Lipids, atherosclerosis and CVD risk:Is CRP an innocent bystander?. Nutrition, Metabolism & Cardiovascular Diseases,2009,19:521-524.
[39]Ridker PM, Danielson E, Fonseca FA, et al. Reduction in C-reactive protein and LDL cholesterol and cardiovascular event rates after initiation of rosuvastatin:a prospective study of the JUPITER trial. Lancet,2009,373:1175-1182.
[40]Zacho J, Tybjaerg-Hansen A, Jensen JS, et al. Genetically elevated C-reactive protein and ischemic vascular disease. N Engl J Med,2008,359:1897-1908.
[41]Hingorani AD, Shah T, Casas JP, et al. C-reactive protein and coronary heart disease: predictive test or therapeutic target? Clin Chem,2009,55:239-255.
[42]Vincenzo Pasceri,Jed Chang,James T. Willerson, et al. Modulation of C-Reactive Protein-Mediated Monocyte Chemoattractant Protein-1 Induction in Human Endothelial Cells by Anti-Atherosclerosis Drugs. Circulation,2001,103:2531-2534.
[43]Ki Hoon Han,Kyung-Hee Hong,Jae-Hyeong Park,et al. C-Reactive Protein Promotes Monocyte Chemoattractant Protein-1-Mediated Chemotaxis Through Upregulating CC Chemokine Receptor 2 Expression in Human Monocytes. Circulation.2004,109:2566-2571.
[44]Koh KK, Ahn J Y, Han SH,et al. Pleiot ropic effect s of angiotensin Ⅱ receptor blocker in hypertensive patient s [J]. J Am Coll Cardiol,2003,42 (5):905-910.
[2]Sakamoto T, Ishibashi T, Sakamoto N, et al. Endogenous NO blockade enhances tissue factor expression via increased Ca2+ influx through MCP-1 in endothelial cells by monocyte adhesion [J]. Arterioscler Thromb Vasc Biol,2005,25(9):2005-2011.
[3]Park SY, Lee JH, Kim YK, et al. Cilostazol prevents remnant lipoprotein particle-induced monocyte adhesion to endothelial cells by suppression of adhesion molecules and monocyte chemoattractant protein-1 expression via lectin-like receptor for oxidized low-density lipoprotein receptor activation [J]. Pharmacol Exp Ther,2005,312(3):1241-1248.
[4]Coll B,Alonso-Villaverde C,Joven J.Monocyte chemoattractant protein-1 and atherosclero-sis:is there room for an additional biomarker? Clin Chim Acta,2007,383:21-29.
[5]Provatoriv SI, Aref,eva TI, Kukhtina NB, et al. Markers of inflammation-monocyte chemoattractant protein-1 (MCP-1) and C-reactive protein--in blood of patients with unstable angina pectoris and stable effort angina [J]. Ter Arkh,2006,78 (6):66-69.
[6]Feng XP, Dong WB, Chen XS. Monocyte chemotactic protein-1 expression in coronary atherosclerosis plaque of sudden coronary death patients [J]. Zhanghua Xin Xue Guan Bing Za Zhi,2006,34(7):589-601.
[7]Jialal I,Devaraj S,Venugopal SK.C-reactive protein:risk marker or mediator in athero-thrombosis? Hypertension 2004,44(1):6-11.
[8]Fichtlscherer S,Rosenberger G,Walter DH,et al.Elevated C-reactive protein levels and impaired endothelial vasoreactivity in patients with coronary artery disease. Circulation,2000, 102(9):1000-1006.
[9]Cleland SJ,Sattar N,Petrie JR,et al. Endothelial dysfunction as a possible link between C-reactive protein levels and cardiovascular disease. Clin Sci (Lond),2000,98(5):531-535.
[10]Nabata A, Kuroki M, Ueba H, et al. C-reactive protein induces endothelial cell apoptosis and matrix metalloproteinase-9 production in human mononuclear cells:implications for the destabilization of atherosclerotic plaque. Atherosclerosis,2008,196(1):129-135.
[11]Wang CH, Li SH, Weisel RD, et al. C-reactive protein upregulates angiotensin type 1 receptors in vascular smooth muscle. Circulation,2003,107(13):1783-1790.
[12]Vincenzo Pasceri,Jed Chang,James T. Willerson,et al.Modulation of C-Reactive Protein-Mediated Monocyte Chemoattractant Protein-1 Induction in Human Endothelial Cells by Anti-Atherosclerosis Drugs. Circulation,2001,103:2531-2534.
[13]Ki Hoon Han,Kyung-Hee Hong,Jae-Hyeong Park,et al. C-Reactive Protein Promotes Monocyte Chemoattractant Protein-1-Mediated Chemotaxis Through Upregulating CC Chemokine Receptor 2 Expression in Human Monocytes. Circulation,2004,109:2566-2571.
[14]Koh KK, Ahn J Y, Han SH,et al. Pleiot ropic effect s of angiotensin Ⅱ receptor blocker in hypertensive patients [J]. J Am Coll Cardiol,2003,42 (5):905-910.
[15]杨晓云.抗动脉粥样硬化药对家兔动脉粥样硬化血管壁NF-Kb-DNA结合活性及炎性因子影响的实验研究： [博士学位论文].武汉：华中科技大学,2006年.
[16]Pfeffer MA, McMurray JJ, Velazquez EJ, et al. Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. N Engl J Med, 2003,349(20):1893-1906.
[17]The_ONTARGET_Investigators. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med,2008,358:1547-1559.
[18]Byron J. Hoogwerf. Renin-Angiotensin System Blockade and Cardio-vascular an Renal Protection.Am J Cardiol,2010,105:30-35.
[19]Hiroki Ikeda, Jun Minamikawa, Yoshio Nakamura. Comparison of effects of amlodipine and angiotensin receptor blockers on the intima-media thickness of carotid arterial wall (AAA study:Amlodipine vs. ARB in atherosclerosis study), [J]. Diabetes Research and Clinical Practice,2009,83:50-53.
[20]Erling Falk.Pathogenesis of Atherosclerosis, J Am Coll Cardiol,2006,47:7-12.
[21]Munzel T, Sinning C, Post F,et al. Pathophysiology, diagnosis and prognostic implications of endothelial dysfunction. Ann Med,2008,40(3):180-196.
[22]Dzau VJ. Theodore Cooper lecture:tissue angiotensin and pathobiology of vascular disease: a unifying hypothesis. Hypertension,2001,37:1047-1052.
[23]Fukuda D, Sata M, Ishizaka N, et al. Critical role of bone marrow angiotensin Ⅱ type 1 receptor in the pathogenesis of atherosclerosis in apolipoprotein E deficient mice. Arterioscler Thromb Vasc Biol,2008,28:90-96.
[24]Chrysant SG, Chrysant GS. Clinical experience with angiotensin receptor blockers with particular reference to valsartan. Clin Hypertens (Greenwich),2004,6:445-451.
[25]Libby P. Inflammation in atherosclerosis. Nature,2002,420:868-74.
[26]Pueyo ME,Gonzalez W,Nicoletli A,et al.Angiotensin Ⅱ stimulates endothelial vascular cell adhesion molecular-1 via nuclear factor-kB activtion induced by intracellular oxidative stress[J]. Arterioscler Thromb Vasc Biol,2000,20:645.
[27]Li Jing,Hirose N,Kawamura M,et al.Antiatherogenic effect of angiotensin converting enzyme inhibiter and angiotensin Ⅱ receptor antagonist in the cholesterol fed rabbits[J]. Atherosclerosis,1999,143:315.
[28]Qiying Xie, Ming Sun, Tian-lun Yang,et al. Losartan reduces monocyte chemoattractant protein-1 expression in aortic tissues of 2K1C hypertensive rats. International Journal of Cardiology,2006,110:60-66.
[29]董波,高顺宗,黄定九,等.氯沙坦对动脉粥样硬化兔的MCP-1及基因表达的实验研究.上海免疫学杂志,2002,22(4)；260-262.
[30]Willerson JT,Ridkre PM. Inflammation as a cardiovascular risk factor. Circulation,2004, 109:2-10.
[31]王明毅.替米沙坦对高血压患者血清C反应蛋白的影响.药物与临床.2010,17(2)：59-60.
[32]付军,白晶,冷吉燕,等.替米沙坦对原发性高血压患者左室肥厚及C反应蛋白的干预作用.中国老年学杂志.2008,28：1916-1918.
[33]仝其广编译.内皮下脂蛋白滞留——动脉粥样硬化的始动过程.心血管病学进展,2008,29(1)： 38-40.
[34]Kumiko Arishiro,Masaaki Hoshiga.Angiotensin Receptor-1 Blocker Inhibits Atherosclerotic Changes and Endothelial Disruption of the Aortic Valve in Hypercholesterolemic Rabbits, J Am Coll Cardiol,2007,49:1482-1489.
[35]Ridker PM, Danielson E, Fonseca FA, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl,J Med,2008,359:2195-2207.
[I]Cipollone F,Marini M,Fazia M,et al.Elevated circulating levels of monocytes chemo-attractant protein 1 in patients with restenosis after coronary angioplasty [J]. Arterioscler Thromb Vasc Biol,2001,21(3):327-334.
[2]Harrington JR. The role of MCP-1 in atherosclerosis [J]. Stem Cells,2000,18(1):65-66.
[3]Frisinghelli A, Mafrici A. Regression or reduction in progression of athero-sclerosis, and avoidance of coronary events, with lovastatin in patients with or at high risk of cardiovascular disease:a review. Clin Drug Investig,2007,27:591-604.
[4]Coll B, Alonso-Villaverde C, Joven J. Monocyte chemoattractant protein-1 and atherosclerosis:is there room for an additional biomarker? Clin Chim Acta,2007,383:21-29.
[5]Kusano KF, Nakamura K, Kusano H, et al. Significance of the level of monocyte chemoattractant protein-1 in human atherosclerosis. Circ J,2004,68:671-676.
[6]Harvey EJ, Li N, Ramji DP. Critical role for casein kinase 2 and phosphoinositide-3-kinase in the interferon-gamma-induced expression of monocyte chemoattractant protein-1 and other key genes implicated in atherosclerosis. Arterioscler Thromb Vasc Biol,2007,27:806-812.
[7]Sakamoto T,Ishibashi T,Sakamoto-N,et al.Endogenous NO blockade enhances tissue factor expression via increased Ca2+ influx through MCP-1 in endothelial cells by monocyte adhesion [J]. Arterioscler Thromb Vasc Biol,2005,25(9):2005-2011.
[8]Park SY, Lee JH, Kim YK, et al. Cilostazol prevents remnant lipoprotein particle-induced monocyte adhesion to endothelial cells by suppression of adhesion molecules and monocyte chemoattractant protein-1 expression via lectin-like receptor for oxidized low-density lipoprotein receptor activation [J]. Pharmacol Exp Ther,2005,312(3):1241-1248.
[9]王文勇,唐红卫,张志培.CD34和血管内皮生长因子在人甲状腺癌组织中的表达及微血管密度的病理意义[J].第四军医大学学报(新),2005,25(15).
[10]Weihua Ni,Kensuke Egashira,Shiro Kitamoto,et al. New Anti-Monocyte Chemoattractant Protein-1 GeneTherapy Attenuates Atherosclerosis in Apolipoprotein E-Knockout Mice [J] Circulation,2001,103:2096-2101.
[11]Shujiro Inoue, Kensuke Egashira, Weihua Ni. Anti-Monocyte Chemoattractant Protein-1 Gene Therapy Limits Progression and Destabilization of Established Atherosclerosis in Apolipoprotein E-Knockout Mice. Circulation,2002,106:2700-2706.
[12]Roque M, Kim WJ, GazdoinM, et al. CCR2 deficiency decreases intimal hyperplasia after arterial injury [J].Arterioscler Thromb Vasc Biol,2002,22:554-559.
[13]Bursill CA, Channon KM, Greaves DR. The role of chemokines in athersclerosis:recent evidence from experimental models and population genetics [J]. Curr Opin Lipidol,2004,15 (2):145-149.
[14]Mazzone, S De Servi, IM azzucchelli, et al. Increased concentrations of inflammatory mediators in unstable angina:correlation with serum troponin T [J]. Heart,2001,85:571.
[15]Kervinen H, M anttari M, Kaatinen M, et al. Prognostic usefulness of plasma monocyte macrophage and T lymphocyte 2 activation markers in patients with acute coronary syndromes [J]. Am J Cardiol,2004,94 (8):993-996.
[16]Liuzzo,goronzy JJ,Yang H, et al. monoclonal T-cell proliferation and plaque instability in acute coronary syndromes [J].Circulation,2000,101:2883-2888.
[17]Provatoriv SI,Aref,eva TI,Kukhtina NB,et al.Markers of inflammation-monocyte chemoattractant protein-1 (MCP-1) and C-reactive protein—in blood of patients with unstable angina pectoris and stable effort angina [J]. Ter Arkh,2006,78 (6):66-69.
[18]Park HJ, Chang K, Park CS,et al. Coronary collaterals:The role of MCP-1 during the early phase of acute myocardial infarction[J]. Int J Cardiol,2007.
[19]Feng XP, Dong WB, Chen XS. Monocyte chemotactic protein-1 expression in coronary atherosclerosis plaque of sudden coronary death patients [J]. Zhanghua Xin Xue Guan Bing Za Zhi,2006,34(7):589-601.
[20]吕春美,彭子敬,田国平.单核细胞趋化蛋白-1对不稳定型心绞痛患者近期心血管事件的预测价值[J],医学临床研究,2008,25(4)：664-666.
[21]Frauke S,Czepluch,Bernhard Zweigle, et al. Chemotaxis analysis of circulating mono-cytes in patients with a recent acute coronary syndrome. Atherosclerosis,2009,204:304-308.
[22]Madej A,Okopien B,Kowalski J, et al. Plasma concentra-tions of adhesion molecules and chemokines in patients with essential hypertension [J]. Pharmacol Rep,2005,57 (6):878-881.
[23]Parissis J T,Korovesis S,Giazitzoglou E,et al. Plasma profiles of peripheral monocyte related inflammatory markers in patients with arterial hypertension. Correlations with plasma endothelin-1 [J]. Int J Cardiol,2002,83:13-21.
[24]Prasad A,Koh KK,Schenke WH,et al.Role of angiotensin Ⅱ type 1 receptor in the regulation of cellular adhesion molecules in atherosclerosis[J]. Am Heart J,2001,142:248-253.
[25]谢启应 孙明 杨天伦,等.高血压病患者血清单核细胞趋化因子-1的变化及其与血管紧张素Ⅱ的关系[J],中国现代医学杂志,2003,13(23)：111-112.
[26]Rodriguez-Iturbe B,Ferrebuz A,Vanegas V,et al.Early and sustained inhibition of nuclear factor-kappa B prevents hypertension in spontaneously hypertensive rats [J]. J Pharmacol Exp Ther,2005,315(1):51-57.
[27]Tonnessen T,Florholmen G,Henriksen UL,et al. Cardiopulmonary alterations in mRNA expression for interleukin-lbeta, the interleukin-6 superfamily and CXC-chemokines during development of postischaemic heart failure in the rat [J]. Clin Physiol Funct Imaging,2003,23 (5)：263-268.
[28]刘芳,辛志强,丁春平,等.CHF血清单核细胞趋化蛋白-1的变化及其与脂质过氧化的关系[J],中国临床实用医学,2007,10(1)：21-23.
[29]王斌,赵连友,郑强荪,等.高血压心肌纤维化的发病机制：成纤维细胞在血管紧张素Ⅱ刺激下单核细胞趋化蛋白-1的表达状况.中国临床康复,2004,8(9)：1683-1685.
[30]Schillinger M,Exner M,Amighi J,et al. Joint effects of C-reactive protein and glycated hemoglobin in predicting future cardiovascular events in patients with advanced atherosclerosis. Circulation,2003,108:2323-2328.
[31]Ridker PM,Rifai N,Rose L,et al.Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events. N Engl J Med,2002, 347:1557-1565.
[32]Ridker PM. C-reactive protein:eighty years from discovery to emergence as a major risk marker for cardiovascular disease. Clin Chem,2009,55:209-215.
[33]Hingorani AD,Shah T,Casas JP,et al. C-reactive protein and coronary heart disease: predictive test or therapeutic target? Clin Chem,2009,55:239-255.
[34]Danesh J,Wheeler JG,Hirschfield GM,et al. C-reactive protein and other circulating markers of inflammation in the prediction of coronary heart disease. N Engl J Med,2004,350: 1387-1397.
[35]尹浩晔,马梅,周馨.高敏C反应蛋白、血浆脑钠肽与急性关脉综合症严重程度的关系.山东医药,2009,49(41)：48-49.
[36]Reza Alizadeh Dehnavi,Albert de Roos,Ton J. Rabelink, Elevated CRP levels are associated with increased carotid atherosclerosis independent of visceral obesity. Atherosclerosis,2008,200: 417-423.
[37]Jialal I,Devaraj S,Venugopal SK.C-reactive protein:risk marker or mediator in athero-thrombosis? Hypertension,2004,44(1):6-11.
[38]B.G. Nordestgaard, J. Zacho. Lipids, atherosclerosis and CVD risk:Is CRP an innocent bystander?. Nutrition, Metabolism & Cardiovascular Diseases,2009,19:521-524.
[39]Ridker PM, Danielson E, Fonseca FA, et al. Reduction in C-reactive protein and LDL cholesterol and cardiovascular event rates after initiation of rosuvastatin:a prospective study of the JUPITER trial. Lancet,2009,373:1175-1182.
[40]Zacho J, Tybjaerg-Hansen A, Jensen JS, et al. Genetically elevated C-reactive protein and ischemic vascular disease. N Engl J Med,2008,359:1897-1908.
[41]Hingorani AD, Shah T, Casas JP, et al. C-reactive protein and coronary heart disease: predictive test or therapeutic target? Clin Chem,2009,55:239-255.
[42]Vincenzo Pasceri,Jed Chang,James T. Willerson, et al. Modulation of C-Reactive Protein-Mediated Monocyte Chemoattractant Protein-1 Induction in Human Endothelial Cells by Anti-Atherosclerosis Drugs. Circulation,2001,103:2531-2534.
[43]Ki Hoon Han,Kyung-Hee Hong,Jae-Hyeong Park,et al. C-Reactive Protein Promotes Monocyte Chemoattractant Protein-1-Mediated Chemotaxis Through Upregulating CC Chemokine Receptor 2 Expression in Human Monocytes. Circulation.2004,109:2566-2571.
[44]Koh KK, Ahn J Y, Han SH,et al. Pleiot ropic effect s of angiotensin Ⅱ receptor blocker in hypertensive patient s [J]. J Am Coll Cardiol,2003,42 (5):905-910.