辛伐他汀对急性心肌梗死大鼠血红素加氧酶-1的影响
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摘要
目的:探讨大鼠急性心肌梗死后心肌内血红素加氧酶-1(HO-1)水平变化及辛伐他汀对HO-1表达的影响。
方法:结扎雄性SD大鼠冠状动脉左前降支建立心肌梗死模型,24h后存活大鼠随机分为心肌梗死组(MI组, n=24)、辛伐他汀(Sim组,n=24)和假手术组(Sham组,只穿线不结扎,n=24)。Sim组以辛伐他汀40mg·kg~(-1)·d~(-1)灌胃,MI组和Sham组以等体积生理盐水灌胃。术后24h、7d、28d处死动物(每组每个时间点各处死大鼠8只),RT-PCR及Western Bolt测定心肌非梗死区HO-1 mRNA和蛋白表达水平,并测非梗死区心肌超氧化物岐化酶(SOD)活性,丙二醛(MDA)含量。
结果:HO-1 mRNA和蛋白表达水平均在心肌梗死后24h开始升高,7d达峰,28d恢复至基线水平。三个时间点MI组上述指标均高于Sham组(P<0.05);术后7d和28d Sim组上述指标均高于MI组(P<0.05)。随HO-1 mRNA和蛋白表达水平升高,Sim组较MI组的SOD活性升高,MDA含量降低。
结论:心肌内HO-1水平在急性心肌梗死后28天内呈现动态变化。辛伐他汀可诱导HO-1表达,发挥抗氧化损伤的心脏保护作用。
Objective: To investigate changes of heme oxygenase-1 (HO-1) in cardiomyocytes after acute myocardial infarction and the impact of simvastatin on HO-1 expression in rats.
Methods: Myocardial infarction models were made by anterior descending coronary artery ligation on male SD rats whereas sham group by spurious ligation( Sham, n=24). Survivals were randomized into myocardial infarction( MI, n=24) group and simvastatin( Sim, n=24) group 24 hours after operation. Sim group was treated with simvastatin 40mg·kg~(-1)·d~(-1) via gavage till sacrifice. MI and Sham gourps were gavaged with equal volume of 0.9%NaCl at the same time. Rats were sacrificed at time points of 24 hours, 7 days and 28 days after operation( n=8 for each group at each time point), for the detection of HO-1 mRNA by RT-PCR, HO-1 protein level by Western Bolt, activity of superoxide dismutase (SOD) and content of malondialdehyde (MDA) by spectrophotometric method in non-infarcted zone.
Results: Expression of HO-1 mRNA and protein level increased at 24 hours, peaked at 7 days and decreased to basal levels at 28 days. All the indexes at each time point mentioned above were significantly higher in MI group than those in Sham group. At 7 days and 28 days (P<0.05), the indexes were higher in Sim group than those in MI group (P<0.05). Activity of SOD was increased while content of MDA was decreased in Sim group than those in MI group at 7days and 28days.
Conclusion: The expression of HO-1 changes dynamically within 28 days after acute myocardial infarction. One of the possible mechanism of simvastatin’s antioxidative cardiac protection may be through the induction of HO-1.
方法:结扎雄性SD大鼠冠状动脉左前降支建立心肌梗死模型,24h后存活大鼠随机分为心肌梗死组(MI组, n=24)、辛伐他汀(Sim组,n=24)和假手术组(Sham组,只穿线不结扎,n=24)。Sim组以辛伐他汀40mg·kg~(-1)·d~(-1)灌胃,MI组和Sham组以等体积生理盐水灌胃。术后24h、7d、28d处死动物(每组每个时间点各处死大鼠8只),RT-PCR及Western Bolt测定心肌非梗死区HO-1 mRNA和蛋白表达水平,并测非梗死区心肌超氧化物岐化酶(SOD)活性,丙二醛(MDA)含量。
结果:HO-1 mRNA和蛋白表达水平均在心肌梗死后24h开始升高,7d达峰,28d恢复至基线水平。三个时间点MI组上述指标均高于Sham组(P<0.05);术后7d和28d Sim组上述指标均高于MI组(P<0.05)。随HO-1 mRNA和蛋白表达水平升高,Sim组较MI组的SOD活性升高,MDA含量降低。
结论:心肌内HO-1水平在急性心肌梗死后28天内呈现动态变化。辛伐他汀可诱导HO-1表达,发挥抗氧化损伤的心脏保护作用。
Objective: To investigate changes of heme oxygenase-1 (HO-1) in cardiomyocytes after acute myocardial infarction and the impact of simvastatin on HO-1 expression in rats.
Methods: Myocardial infarction models were made by anterior descending coronary artery ligation on male SD rats whereas sham group by spurious ligation( Sham, n=24). Survivals were randomized into myocardial infarction( MI, n=24) group and simvastatin( Sim, n=24) group 24 hours after operation. Sim group was treated with simvastatin 40mg·kg~(-1)·d~(-1) via gavage till sacrifice. MI and Sham gourps were gavaged with equal volume of 0.9%NaCl at the same time. Rats were sacrificed at time points of 24 hours, 7 days and 28 days after operation( n=8 for each group at each time point), for the detection of HO-1 mRNA by RT-PCR, HO-1 protein level by Western Bolt, activity of superoxide dismutase (SOD) and content of malondialdehyde (MDA) by spectrophotometric method in non-infarcted zone.
Results: Expression of HO-1 mRNA and protein level increased at 24 hours, peaked at 7 days and decreased to basal levels at 28 days. All the indexes at each time point mentioned above were significantly higher in MI group than those in Sham group. At 7 days and 28 days (P<0.05), the indexes were higher in Sim group than those in MI group (P<0.05). Activity of SOD was increased while content of MDA was decreased in Sim group than those in MI group at 7days and 28days.
Conclusion: The expression of HO-1 changes dynamically within 28 days after acute myocardial infarction. One of the possible mechanism of simvastatin’s antioxidative cardiac protection may be through the induction of HO-1.
引文
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[2] Takahashi T, Morita K, Akagi R, Sassa S. Protective role of heme oxygenase-1 in renal ischemia[J]. Antioxid Redox Signal, 2004, 6(5):867-77.
[3] Brunt KR, Tsuji MR, Lai JH, et al. Heme Oxygenase-1 Inhibits Pro-Oxidant Induced Hypertrophy In HL-1 Cardiomyocytes[J]. Exp Biol Med (Maywood).,2009, 234:582-94.
[4] Liu X, Simpson JA, Brunt KR, et al. Preemptive heme oxygenase-1 gene delivery reveals reduced mortality and preservation of left ventricular function 1 yr after acute myocardial infarction[J]. Am J Physiol Heart Circ Physiol, 2007, 293(1):H48-59.
[5] Chen SM, Li YG, Wang DM, et al. Expression of heme oxygenase-1, hypoxia inducible factor-1alpha, and ubiquitin in peripheral inflammatory cells from patients with coronary heart disease[J]. Clin Chem Lab Me, 2009;47:327–33.
[6] Zhang S, Lu S, Ge J, et al. Increased heme oxygenase-1 expression in infarcted rat hearts following human bone marrow mesenchymal cell transplantation[J]. Microvasc Res, 2005, 69(1-2):64-70.
[7] Lakkisto P, Palojoki E, Backlund T, et al. Expression of heme oxygenase-1 in response to myocardial infarction in rats[J]. J Mol Cell Cardiol, 2002, 34(10):1357-65.
[8] Comparato C, Altana C, Bellosta S, et al. Clinically relevant pleiotropic effects of statins: drug properties or effects of profound cholesterol reduction[J]? Nutr Metab Cardiovasc Dis, 2001, 11(5):328-43.
[9] Immenschuh S, Schroder H. Heme oxygenase-1 and cardiovascular disease[J]. Histol Histopathol, 2006, 21(6):679-85.
[10] Forstermann U. Oxidative stress in vascular disease: causes, defense mechanismsand potential therapies[J]. Nat Clin Pract Cardiovasc Med, 2008, 5(6):338-49.
[11] Ruperez M, Rodrigues-Diez R, Blanco-Colio LM, et al. HMG-CoA reductase inhibitors decrease angiotensin II-induced vascular fibrosis: role of RhoA/ROCK and MAPK pathways[J]. Hypertension, 2007, 50(2):377-83.
[12] Lee TS, Chang CC, Zhu Y, Shyy JY. Simvastatin induces heme oxygenase-1: a novel mechanism of vessel protection[J]. Circulation, 2004, 110(10):1296-302.
[13] Chen JC, Huang KC, Lin WW. HMG-CoA reductase inhibitors upregulate heme oxygenase-1 expression in murine RAW264.7 macrophages via ERK, p38 MAPK and protein kinase G pathways[J]. Cell Signal, 2006, 18(1):32-9.
[14] Hsu M, Muchova L, Morioka I, et al. Tissue-specific effects of statins on the expression of heme oxygenase-1 in vivo[J]. Biochem Biophys Res Commun, 2006, 343(3):738-44.
[15] Grosser N, Hemmerle A, Berndt G, et al. The antioxidant defense protein heme oxygenase 1 is a novel target for statins in endothelial cells[J]. Free Radic Biol Med, 2004, 37(12):2064-71.
[16] Pfeffer JM, Pfeffer MA, Braunwald E. Influence of chronic captopril therapy on the infarcted left ventricle of the rat[J]. Circ Res, 1985, 57(1):84-95.
[17]覃数,陈运贞.大白鼠实验性心肌缺血再灌注模型制备与心电图改变的特点[J].重庆医科大学学报, 1998, 23(1):8-11.
[18] Ueyama T, Kawabe T, Hano T, et al. Upregulation of Heme Oxygenase-1 in an Animal Model of Takotsubo Cardiomyopathy[J]. Circ J, 2009, Apr 16.
[19] Zhang S, Lu S, Ge J, et al. Increased heme oxygenase-1 expression in infarcted rat hearts following human bone marrow mesenchymal cell transplantation[J]. Microvasc Res, 2005, 69(1-2):64-70.
[20] Liu X, Pachori AS, Ward CA, et al. Heme oxygenase-1 (HO-1) inhibits postmyocardial infarct remodeling and restores ventricular function[J]. FASEB J, 2006, 20(2):207-16.
[21] Dreger H, Westphal K, Weller A, et al. Nrf2-dependent upregulation of antioxidative enzymes - a novel pathway for proteasome inhibitor-mediatedcardioprotection[J]. Cardiovasc Res, 2009 Apr 7.
[22] Burger D, Xiang F, Hammoud L,et al. Role of heme oxygenase-1 in the cardioprotective effects of erythropoietin during myocardial ischemia and reperfusion[J]. Am J Physiol Heart Circ Physiol, 2009, 296(1):H84-93.
[23] Velmurugan K, Alam J, McCord JM,et al. Synergistic induction of heme oxygenase-1 by the components of the antioxidant supplement Protandim[J]. Free Radical Biology and Medicine, 2009, 46(3):430-40.
[24] Brandsma CA, Hylkema MN, van der Strate BW, et al. Heme oxygenase-1 prevents smoke induced B-cell infiltrates: a role for regulatory T cells[J]?. Respir Res, 2008, 9:17.
[25] Grosser N, Erdmann K, Hemmerle A, et al. Rosuvastatin upregulates the antioxidant defense protein heme oxygenase-1[J]. Biochem Biophys Res Commun, 2004, 325(3):871-6.
[26] Gueler F, Park JK, Rong S, et al. Statins attenuate ischemia-reperfusion injury by inducing heme oxygenase-1 in infiltrating macrophages[J]. Am J Pathol, 2007, 170(4):1192-9.
[27] Ishii T, Itoh K, Ruiz E, et al. Role of Nrf2 in the regulation of CD36 and stress protein expression in murine macrophages: activation by oxidatively modified LDL and 4-hydroxynonenal[J]. Circ Res, 2004, 94(5):609-16.
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