缬沙坦调节兔动脉粥样硬化血管过氧化物酶体增殖物激活受体γ表达改善炎症反应
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摘要
目的:研究血管紧张素Ⅱ1型受体拮抗剂缬沙坦对实验性兔动脉粥样硬化形成,以及对主动脉单核细胞趋化蛋白-1(MCP-1)和过氧化物酶体增殖物激活受体γ(PPARγ)的影响。
方法: 24只雄性新西兰白兔随机分为3组:对照组,动脉粥样硬化(AS)造模组,缬沙坦组,喂养12周。进行血脂测定,主动脉内膜/中膜比值测定,免疫组化方法检测各组主动脉MCP-1和PPARγ蛋白,RT-PCR检测MCP-1和PPARγmRNA的表达。
结果:缬沙坦组及AS造模组的血清胆固醇、甘油三酯、低密度脂蛋白胆固醇均无差异(各P>0.05) ,但均高于对照组(P<0.01)。缬沙坦组内膜/中膜厚度比值较AS造模组明显减少(P<0.05)。AS造模组动脉粥样硬化血管组织MCP-1蛋白和mRNA的表达较对照组明显增多(P<0.05),而缬沙坦组动脉粥样硬化血管组织MCP-1蛋白和mRNA的表达较AS造模组明显减少(P<0.05),缬沙坦组动脉粥样硬化血管组织PPARγ蛋白和mRNA的表达较AS造模组明显增加(P<0.05)。
结论:缬沙坦抑制兔动脉粥样硬化形成,并抑制动脉粥样硬化血管MCP-1,说明它具有抗炎作用,其抗炎作用可能与其增加动脉粥样硬化血管组织PPARγ有关。
Objective: To study the effect of Valsartan on the expression of monocyte chemoattractant protein-1(MCP-1) and peroxisome proliferator activated receptor gamma (PPARγ) in experimental atherosclerotic rabbits.
Methods: Twenty four male New Zealand rabbits were randomly divided into 3 group : group 1: normal rabbit chow, group 2: cholesterol diet, group 3: cholesterol diet supplemented by Valsartan. All rabbits were fed according to experiment design for 12 weeks. Blood samples were obtained from vein for detection of serum lipid. The intima-media thickness was measured. The expression of MCP-1 and PPARγwere examined by immunohistochemistry and reverse transcription polymerase chain reaction.
Results: Levels of serum TC、TG、LDL-C in group 2 and 3 were significant higher than those of group 1(P<0.05), but it has no significant difference between group 2 and 3 (P>0.05). The ratio of intima-media reduced obviously in group 3 than those of group 2 (P<0.05). The expression of MCP-1 was higher in group 2 than group 1 and group3 (P<0.05). The expression of PPARγwas higher in group 3 than group 2(P< 0.05). Conclusion: These findings suggest that Valsartan could affect atherosclerosis and the MCP-1 expression in experimental atherosclerotic rabbits which are probably related to its activating effect of PPARγ.
方法: 24只雄性新西兰白兔随机分为3组:对照组,动脉粥样硬化(AS)造模组,缬沙坦组,喂养12周。进行血脂测定,主动脉内膜/中膜比值测定,免疫组化方法检测各组主动脉MCP-1和PPARγ蛋白,RT-PCR检测MCP-1和PPARγmRNA的表达。
结果:缬沙坦组及AS造模组的血清胆固醇、甘油三酯、低密度脂蛋白胆固醇均无差异(各P>0.05) ,但均高于对照组(P<0.01)。缬沙坦组内膜/中膜厚度比值较AS造模组明显减少(P<0.05)。AS造模组动脉粥样硬化血管组织MCP-1蛋白和mRNA的表达较对照组明显增多(P<0.05),而缬沙坦组动脉粥样硬化血管组织MCP-1蛋白和mRNA的表达较AS造模组明显减少(P<0.05),缬沙坦组动脉粥样硬化血管组织PPARγ蛋白和mRNA的表达较AS造模组明显增加(P<0.05)。
结论:缬沙坦抑制兔动脉粥样硬化形成,并抑制动脉粥样硬化血管MCP-1,说明它具有抗炎作用,其抗炎作用可能与其增加动脉粥样硬化血管组织PPARγ有关。
Objective: To study the effect of Valsartan on the expression of monocyte chemoattractant protein-1(MCP-1) and peroxisome proliferator activated receptor gamma (PPARγ) in experimental atherosclerotic rabbits.
Methods: Twenty four male New Zealand rabbits were randomly divided into 3 group : group 1: normal rabbit chow, group 2: cholesterol diet, group 3: cholesterol diet supplemented by Valsartan. All rabbits were fed according to experiment design for 12 weeks. Blood samples were obtained from vein for detection of serum lipid. The intima-media thickness was measured. The expression of MCP-1 and PPARγwere examined by immunohistochemistry and reverse transcription polymerase chain reaction.
Results: Levels of serum TC、TG、LDL-C in group 2 and 3 were significant higher than those of group 1(P<0.05), but it has no significant difference between group 2 and 3 (P>0.05). The ratio of intima-media reduced obviously in group 3 than those of group 2 (P<0.05). The expression of MCP-1 was higher in group 2 than group 1 and group3 (P<0.05). The expression of PPARγwas higher in group 3 than group 2(P< 0.05). Conclusion: These findings suggest that Valsartan could affect atherosclerosis and the MCP-1 expression in experimental atherosclerotic rabbits which are probably related to its activating effect of PPARγ.
引文
[1] Libby P, Ridker PM, Maseri A. Inflammation and atherosclerosis.Circulation, 2002, 105(9):1135-1143.
[2] Reape TJ, Groot PH. Chemokines and atherosclerosis. Atherosclerosis, 1999, 147(2): 213-225.
[3] Libby P. Current concepts of the pathogenesis of the acute coronary syndrome. Circulation, 2001, 104(3):365-372.
[4] Proudfoot JM, Croft KD, Puddey IB, et al. Angiotensin II type 1 receptor antagonists inhibit basal as well as low-density lipoprotein and platelet-activating factor-stimulated human monocyte chemoattractant protein-1. J Pharmacol Exp Ther, 2003, 305(3): 846-53.
[5] Staels B. PPAR gamma and atherosclerosis. Curr Med Res Opin, 2005, 21 Suppl 1: S13-S20.
[6] Miyazaki M , Takai S. Involvement of angiotensinⅡin development of atherosclerosis. Nippon Rinsho, 2002, 60(10): 1904-10.
[7] Papademeriou V. The potential role of AT (1)-receptor blockade in the prevention and reversal of atherosclerosis. J Hum Hypertens, 2002, 16 (Suppl 3): s34-41.
[8] Johnstone MT, Perez AS, Nasser I, et al. Angiotensin receptor blockade with cande- sartan attenuates atherosclerosis, plaque disruption, and macrophage accumulation within the plaque in a rabbit model .Circulation, 2004, 110(14): 2060–65.
[9] Takai S, Jin D, Sakaguchi M, et al. The regressive effect of an angiotensinⅡreceptor blocker on formed fatty streaks in monkeys fed a high-cholesterol diet. J Hypertens, 2005, 23(10):1879-86.
[10] Waseda K, Ozaki Y, Takashima H, et al. Impact of angiotensinⅡreceptor blockers on the progression and regression of coronary atherosclerosis: an intravascular ultrasound study.Circ J, 2006, 70(9):1111-5.
[11] Ni W, Kitamoto S, Ishibashi M, et al. Monocyte chemoattractant protein-1 is an essential inflammatory mediator in angiotensinⅡ-induced progression of established atherosclerosis in hypercholesterolemic mice. Arterioscler Thromb Vasc Biol, 2004, 24(3):534-9.
[12]董波,黄定九,李惠丽,等.血管紧张素Ⅱ对单核细胞趋化因子及黏附分子表达的影响.上海免疫学杂志,2002, 22(2):104-106.
[13]董波,黄定九,陈玉英,等.氯沙坦对动脉粥样硬化兔影响的实验研究.上海第二医科大学学报,2002, 22(2):128-130.
[14] Cheng ZJ, Vapaatalo H, Mervaala E. AngiotensinⅡand vascular inflammation. Med Sci Monit, 2005, 11(6): RA194-205.
[15] Proudfoot JM, Croft KD, Puddey IB, et al. AngiotensinⅡtype 1 receptor antagonists inhibit basal as well as low-density lipoprotein and platelet-activating factor-stimulated human monocyte chemoattractant protein-1. J Pharmacol Exp Ther, 2003, 305(3): 846-853.
[16] Kato M, Sada T, Chuma H, et al. Severity of hyperlipidemia does not affect antiatherosclerotic effect of an angiotensinⅡreceptor antagonist in apolipoprotein E-deficient mice. J Cardiovasc Pharmacol, 2006, 47(6): 764-9.
[17] Kota BP, Huang TH,Roufogalis BD. An overview on biological mechanisms of PPARs. Pharmacol Res, 2005, 51(2):85-94.
[18] Hsueh WA, Law RE. PPARgamma and atherosclerosis: effects on cell growth and movement. Arterioscler Thromb Vasc Biol, 2001, 21(12):1891-5.
[19] Ishibashi M, Egashira K, Hiasa K, et al. Antiinflammatory and antiarteriosclerotic effects of pioglitazone. Hypertension, 2002, 40(5): 687-693.
[20]李春晖,谭茗月,张新超.激活过氧化物酶增殖物激活受体对血管紧张素Ⅱ诱导内皮细胞中单核细胞趋化因子-1表达的影响.中华老年医学杂志, 2006, 25(9): 664-667.
[21] Schupp M, Janke J, Clasen R, et al. Angiotensin type 1 receptor blockers induceperoxisome proliferator-activated receptor-gamma activity. Circulation, 2004, 109(17): 2054-57.
[22] Benson SC, Pershadsingh HA, Ho CI, et al. Identification of telmisartan as a unique angiotensinⅡreceptor antagonist with selective PPARgamma-modulating activity. 2004, 43(5): 993-1002.
[23] Marx N, Duez H, Fruchart JC, et al. Peroxisome proliferator-activated receptors and atherogenesis: regulators of gene expression in vascular cells. Circ Res, 2004, 94(9): 1168-1178.
[24] Dandona P, Kumar V, Aljada A, et al. AngiotensinⅡreceptor blocker valsartan suppresses reactive oxygen species generation in leukocytes, nuclear factor-kappa B, in mononuclear cells of normal subjects: evidence of an antiinflammatory action. J Clin Endocrinol Metab, 2003, 88(9): 4496-4501.
[25]王海蓉,李建军,蒋锡嘉,等.血管紧张素Ⅱ对培养血管内皮细胞核因子-κB激活及厄贝沙坦干预研究.中华心血管病杂志, 2004, 32(1): 64-67.
[26] Kim YS, Han CY, Kim SW, et al. The orphan nuclear receptor small heterodimer partner as a novel coregulator of nuclear factor-kappa in oxidized low density lipoprotein-treated macrophage cell line RAW 264.7. J Biol Chem, 2001, 276(36): 33736-40.
[27] Julius S, Kjeldsen SE, Weber M, et al. Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomised trial. Lancet, 2004, 363(9426):2022-31.
[28] 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):1893-906.
[29] McMurray J, Solomon S, Pieper K,et al. The effect of valsartan, captopril, or both on atherosclerotic events after acute myocardial infarction: an analysis of the Valsartan in Acute Myocardial Infarction Trial (VALIANT). J Am Coll Cardiol, 2006, 47(4): 726-33.
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[3] Neve BP, Fruchart JC, Staels B. Role of the peroxisome proliferators activated receptors(PPAR) in atherosclerosis. Biochem Pharmacol, 2000, 60(8):1245-50.
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[5] Ishibashi M, Egashira K, Hiasa K, et al. Antiinflammatory and antiarteriosclerotic effects of pioglitazone. Hypertension, 2002, 40(5): 687-693.
[6] Wang N, Verna L, Chen NG, et al. Constitutive activation of peroxisome proliferator-activated receptor-gamma suppresses pro-inflammatory adhesion molecules in human vascular endothelial cells. J Biol Chem,2002, 277(37): 34176-34181.
[7] Verrier E, Wang L, Wadham C,et a1.PPARgamma agonists ameliorate endothelial cell activation via inhibition of diacylglycerol-protein kinase C signaling pathway: role of diacylglycerol kinase. Circ Res, 2004, 94(11): 1515-22.
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[35] Schupp M, Janke J, Clasen R, et al. Angiotensin type 1 receptor blockers induce peroxisome proliferator-activated receptor-gamma activity. Circulation, 2004, 109(17): 2054-2057.
[2] Reape TJ, Groot PH. Chemokines and atherosclerosis. Atherosclerosis, 1999, 147(2): 213-225.
[3] Libby P. Current concepts of the pathogenesis of the acute coronary syndrome. Circulation, 2001, 104(3):365-372.
[4] Proudfoot JM, Croft KD, Puddey IB, et al. Angiotensin II type 1 receptor antagonists inhibit basal as well as low-density lipoprotein and platelet-activating factor-stimulated human monocyte chemoattractant protein-1. J Pharmacol Exp Ther, 2003, 305(3): 846-53.
[5] Staels B. PPAR gamma and atherosclerosis. Curr Med Res Opin, 2005, 21 Suppl 1: S13-S20.
[6] Miyazaki M , Takai S. Involvement of angiotensinⅡin development of atherosclerosis. Nippon Rinsho, 2002, 60(10): 1904-10.
[7] Papademeriou V. The potential role of AT (1)-receptor blockade in the prevention and reversal of atherosclerosis. J Hum Hypertens, 2002, 16 (Suppl 3): s34-41.
[8] Johnstone MT, Perez AS, Nasser I, et al. Angiotensin receptor blockade with cande- sartan attenuates atherosclerosis, plaque disruption, and macrophage accumulation within the plaque in a rabbit model .Circulation, 2004, 110(14): 2060–65.
[9] Takai S, Jin D, Sakaguchi M, et al. The regressive effect of an angiotensinⅡreceptor blocker on formed fatty streaks in monkeys fed a high-cholesterol diet. J Hypertens, 2005, 23(10):1879-86.
[10] Waseda K, Ozaki Y, Takashima H, et al. Impact of angiotensinⅡreceptor blockers on the progression and regression of coronary atherosclerosis: an intravascular ultrasound study.Circ J, 2006, 70(9):1111-5.
[11] Ni W, Kitamoto S, Ishibashi M, et al. Monocyte chemoattractant protein-1 is an essential inflammatory mediator in angiotensinⅡ-induced progression of established atherosclerosis in hypercholesterolemic mice. Arterioscler Thromb Vasc Biol, 2004, 24(3):534-9.
[12]董波,黄定九,李惠丽,等.血管紧张素Ⅱ对单核细胞趋化因子及黏附分子表达的影响.上海免疫学杂志,2002, 22(2):104-106.
[13]董波,黄定九,陈玉英,等.氯沙坦对动脉粥样硬化兔影响的实验研究.上海第二医科大学学报,2002, 22(2):128-130.
[14] Cheng ZJ, Vapaatalo H, Mervaala E. AngiotensinⅡand vascular inflammation. Med Sci Monit, 2005, 11(6): RA194-205.
[15] Proudfoot JM, Croft KD, Puddey IB, et al. AngiotensinⅡtype 1 receptor antagonists inhibit basal as well as low-density lipoprotein and platelet-activating factor-stimulated human monocyte chemoattractant protein-1. J Pharmacol Exp Ther, 2003, 305(3): 846-853.
[16] Kato M, Sada T, Chuma H, et al. Severity of hyperlipidemia does not affect antiatherosclerotic effect of an angiotensinⅡreceptor antagonist in apolipoprotein E-deficient mice. J Cardiovasc Pharmacol, 2006, 47(6): 764-9.
[17] Kota BP, Huang TH,Roufogalis BD. An overview on biological mechanisms of PPARs. Pharmacol Res, 2005, 51(2):85-94.
[18] Hsueh WA, Law RE. PPARgamma and atherosclerosis: effects on cell growth and movement. Arterioscler Thromb Vasc Biol, 2001, 21(12):1891-5.
[19] Ishibashi M, Egashira K, Hiasa K, et al. Antiinflammatory and antiarteriosclerotic effects of pioglitazone. Hypertension, 2002, 40(5): 687-693.
[20]李春晖,谭茗月,张新超.激活过氧化物酶增殖物激活受体对血管紧张素Ⅱ诱导内皮细胞中单核细胞趋化因子-1表达的影响.中华老年医学杂志, 2006, 25(9): 664-667.
[21] Schupp M, Janke J, Clasen R, et al. Angiotensin type 1 receptor blockers induceperoxisome proliferator-activated receptor-gamma activity. Circulation, 2004, 109(17): 2054-57.
[22] Benson SC, Pershadsingh HA, Ho CI, et al. Identification of telmisartan as a unique angiotensinⅡreceptor antagonist with selective PPARgamma-modulating activity. 2004, 43(5): 993-1002.
[23] Marx N, Duez H, Fruchart JC, et al. Peroxisome proliferator-activated receptors and atherogenesis: regulators of gene expression in vascular cells. Circ Res, 2004, 94(9): 1168-1178.
[24] Dandona P, Kumar V, Aljada A, et al. AngiotensinⅡreceptor blocker valsartan suppresses reactive oxygen species generation in leukocytes, nuclear factor-kappa B, in mononuclear cells of normal subjects: evidence of an antiinflammatory action. J Clin Endocrinol Metab, 2003, 88(9): 4496-4501.
[25]王海蓉,李建军,蒋锡嘉,等.血管紧张素Ⅱ对培养血管内皮细胞核因子-κB激活及厄贝沙坦干预研究.中华心血管病杂志, 2004, 32(1): 64-67.
[26] Kim YS, Han CY, Kim SW, et al. The orphan nuclear receptor small heterodimer partner as a novel coregulator of nuclear factor-kappa in oxidized low density lipoprotein-treated macrophage cell line RAW 264.7. J Biol Chem, 2001, 276(36): 33736-40.
[27] Julius S, Kjeldsen SE, Weber M, et al. Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomised trial. Lancet, 2004, 363(9426):2022-31.
[28] 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):1893-906.
[29] McMurray J, Solomon S, Pieper K,et al. The effect of valsartan, captopril, or both on atherosclerotic events after acute myocardial infarction: an analysis of the Valsartan in Acute Myocardial Infarction Trial (VALIANT). J Am Coll Cardiol, 2006, 47(4): 726-33.
[1] Ross R. Atheroslerosis-an inflammatory disease. N Engl J Med, 1999, 340(2):115- 126.
[2] Hsueh WA, Law RE. PPARgamma and atherosclerosis: effects on cell growth and movement. Arterioscler Thromb Vasc Biol, 2001, 21(12):1891-5.
[3] Neve BP, Fruchart JC, Staels B. Role of the peroxisome proliferators activated receptors(PPAR) in atherosclerosis. Biochem Pharmacol, 2000, 60(8):1245-50.
[4] Li AC, Brown KK, Silvestre MJ, et a1. Peroxisome proliferator-activated receptor gamma ligands inhibit development of atherosclerosis in LDL receptor-deficient mice. J Clin Invest, 2000, 106(4): 523-531.
[5] Ishibashi M, Egashira K, Hiasa K, et al. Antiinflammatory and antiarteriosclerotic effects of pioglitazone. Hypertension, 2002, 40(5): 687-693.
[6] Wang N, Verna L, Chen NG, et al. Constitutive activation of peroxisome proliferator-activated receptor-gamma suppresses pro-inflammatory adhesion molecules in human vascular endothelial cells. J Biol Chem,2002, 277(37): 34176-34181.
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