Objective:To observe the expression of matrix metalloproteinase(MMP)-2 and tissue inhibitors of metalloproteinase(TIMP)-2 in rabbits model with atherosclerosis.Method:The 27 healthy male pure New Zealand rabbits were randomly divided into control group,model group and rosiglitazone group.After 10weeks of the experiment,enzymology method was used to detect the levels of serum lipid.The expressions of the histopathology and protein of MMP-2 and TIMP-2 in atherosclerotic plaques of the aorta were observed by immunohistochemistry technique.Result:Compared with the model group,rabbit aorta atherosclerotic plaque and foam cells decreased,MMP-2 decreased,TIMP-2increased in rosiglitazone group(P<0.05).Conclusion:Rosiglitazone could downregulate MMP-2and upregulate TIMP-2 in rabbits with atherosclerosis.

目的 通过比较罗格列酮和辛伐他汀对动脉粥样硬化兔炎症因子的影响,探讨其抗动脉粥样硬化的作用机制.方法 36只雄性新西兰大白兔随机分为对照组、模型组、辛伐他汀组、罗格列酮组,采用皮下注射同型半胱氨酸硫内酯及高脂饮食相结合的方法建立动脉粥样硬化模型,酶联免疫吸附法检测血清白介素-18水平,免疫组化技术测定主动脉粥样斑块中单核细胞趋化蛋白-1和基质金属蛋白酶-9的表达.结果 与对照组比较,其他3组血清白介素-18水平、主动脉粥样斑块中单核细胞趋化蛋白-1和基质金属蛋白酶-9表达显著增高(P＜0.05)；罗格列酮组和辛伐他汀组白介素-18水平、单核细胞趋化蛋白-1和基质金属蛋白酶-9表达较模型组明显降低(P＜0.05).罗格列酮组白介素-18较辛伐他汀组降低明显(P＜0.05),单核细胞趋化蛋白-1和基质金属蛋白酶-9的表达在两组间无统计学差异(P＞0.05).结论 罗格列酮可降低动脉粥样硬化兔血清IL-18和主动脉粥样斑块中单核细胞趋化蛋白-1和基质金属蛋白酶-9的表达,抑制动脉粥样硬化的进展,其机制与抗炎作用有关.

目的 观察罗格列酮对RAW264.7巨噬源性泡沫细胞形成中胆固醇含量及酰基辅酶A-胆固醇酰基转移酶-1 (acyl coenzyme A cholesterol acyl transfer enzyme 1,ACAT-1)、三磷酸腺苷结合盒转运蛋白A-1 (ATP combination box of transporter 1,ABCA-1)表达的影响,探讨罗格列酮对泡沫细胞形成的影响及可能的作用机制.方法 在DMEM高糖培养基中培养RAW264.7巨噬细胞,按完全随机分组方法分为:①空白对照组(常规培养基培养巨噬细胞)；②氧化低密度脂蛋白(oxidized low density lipoprotein,oxLDL)组(用终浓度为30 mg/L的oxLDL孵育48 h)；③oxLDL+罗格列酮组(分别用终浓度5、10、20 μmol/L的罗格列酮+30 mg/L oxLDL共同孵育48 h)(n=10).采用油红O染色观察泡沫细胞,胆固醇检测试剂盒测定各组细胞内总胆固醇(total cholesterol,TC)和游离胆固醇(free cholesterol,FC)的含量,Western blot法检测各组细胞ACAT-1和ABCA1的表达水平.结果oxLDL组中大量泡沫细胞的胞质被油红O染色,oxLDL+罗格列酮组泡沫细胞胞质染色明显浅于oxLDL组的细胞;与oxLDL组相比,oxLDL+罗格列酮组TC及FC显著降低(P＜0.05),且呈浓度依赖性；Western blot检测结果表明,不同浓度(5、10、20 μmol/L)oxLDL+罗格列酮组ACAT-1蛋白表达分别为(0.94±0.11)、(0.86±0.13)、(0.58 ±0.12),与oxLDL组(1.19 ±0.12)相比有显著差异(P＜0.05),不同浓度oxLDL+罗格列酮组ABCA1蛋白表达分别为(0.72±0.08)、(0.91 ±0.15)、(1.15±0.11),与oxLDL组(0.63 ±0.05)相比有显著差异(P＜0.05),且呈浓度依赖性.结论 罗格列酮可能通过抑制ACAT-1的表达及促进ABCA-1的表达减少泡沫细胞形成,从而发挥其抗动脉粥样硬化的作用.

Objective:To compare the effects of rosiglitazone and simvastatin on the expressions of interleukin(IL)-6 and interleukin(IL)-8 in atherosclerotic rabbit model and to explore the anti-atherosclerotic properties of rosiglitazone.Methods:A total of 36 male New Zealand rabbits were randomly divided into control group,model group,simvastatin group and rosiglitazone group.Subcutaneous injection of dl-homocysteine thiolactone(HTL) with cholesterol-enriched diet was used to reproduce atherosclerotic rabbit model.Serum IL-6 and IL-8 were examined at the method of enzyme-linked immunosorbent assay(ELISA) at the end of 10 weeks.Immunohistochemistry staining was performed to observe IL-6 and IL-8 protein expressions in each group.Results:The experimental results both in the serum and in the diseased region have shown that compared with the control group,the IL-6 and IL-8 expressions were significantly increased in the other three groups(P0.05).Compared with the model group,the expressions of IL-6 and IL-8 in the simvastatin group and the rosiglitazone group were decreased significantly(P0.05).The expressions of IL-6 and IL-8 in the rosiglitazone group were decreased significantly when compared with the simvastatin group(P0.05).Conclusion:Rosiglitazone may reduce the expression of the inflammatory factors such as IL-6 and IL-8 both in the serum and in the diseased region,and alleviate the inflammatory reaction contributing to atherosclerosis.

Objective:To explore the anti-atherosclerotic mechanism of rosiglitazone by comparing the effects of rosiglitazone and simvastatin on the expressions of matrix metalloproteinase(MMP)-2 and tissue inhibitors of metalloproteinase(TIMP)-2 in atherosclerotic rabbit model.Methods:Thirty-six male New Zealand rabbits were randomly divided into control group,model group,simvastatin group and rosiglitazone group.Subcutaneous injection of dl-homocysteine thiolactone(HTL)with high fat feeding was conducted to reproduce atherosclerotic rabbit model.Enzyme-linked immunosorbent assay(ELISA) and immunohistochemistry staining were performed to detect the serum levels of ox-LDL and sCD40L,and MMP-2 and TIMP-2 protein expressions,respectively.Results:Compared with the control group,the MMP-2 expression was significantly increased and the TIMP-2 expression was significantly decreased in the other three groups(P0.05).Compared with the model group,the expressions of MMP-2 protein in the simvastatin group and the rosiglitazone group were decreased significantly,but the expressions of TIMP-2 protein were increased significantly(P0.05);serum levels of ox-LDL and sCD40L were decreased significantly.However,the parameters mentioned above were similar between simvastatin group and rosiglitazone group(P0.05).Conclusion:Rosiglitazone could downregulate the expression of MMP-2 and upregulate the expression of TIMP-2,reduce serum levels of ox-LDL and sCD40L,and alleviate the inflammatory reaction associated with atherosclerosis.

OBJECTIVE:To observe the effect of rosiglitazone on the content of cholesterol and expressions of Acy-coenzyme A: cholesterol acyltransferase 1 (ACAT-1) and scavenger receptor class B type I (SR-BI) in RAW264.7 macrophage-derived foam cells and explore the anti-atherosclerotic mechanism of rosiglitazone. METHODS:RAW264.7 macrophages were incubated with oxidized low-density lipoproteins (ox-LDL) or with both ox-LDL and rosiglitazone (5, 10, or 20 µmol/L). Oil red O staining was used to observe the formation of foam cells, and cholesterol oxidase was used to determine the content of cellular cholesterol contents. Western blotting was used observe the expressions of ACAT-1 and SR-BI in RAW264.7 foam cells. RESULTS:Compared with the control cells, RAW264.7 macrophage-derived foam cells showed significantly increased contents of total cholesterol and free cholesterol (P<0.01) and ACAT-1 expressions (P<0.05) with mildly increased SR-BI expression (P>0.05). Rosiglitazone treatments significantly lowered the contents of total cholesterol and free cholesterol (P<0.05), decreased the expression of ACAT-1 (P<0.05), and increased SR-BI expression (P<0.05) in the foam cells in a dose-dependent manner. CONCLUSION:Rosiglitazone can decrease the contents of total and free cholesterol, down-regulate ACAT-1 expression and up-regulate SR-BI expression in the foam cells produce the anti-atherosclerotic effect.

Objective:In order to explore carbamylated erythropoietin(CEPO)'s effect in chronic heart failure(CHF)area,besides many studies have already shown CEPO has clearly cardioprotective effect in other areas.Levels of serum Matrix Metalloproteinase-2(MMP-2),Tissue Inhibitor of Metalloproteinase-1(TIMP-1) and Volume Fraction of Collagen(CVF) were assessed to reflect whether CEPO has cardioprotective effect in rats with CHF and its possible mechanisms.Method:10 of 80 Wistar rats have been randomly selected as control group,other 70 rats were injected with isoprenaline intraperitonealy to establish CHF models.After nine weeks,when CHF models were established successfully,CHF rats were divided into two groups,CHF group(n=18) and CEPO group(n=18).CEPO group were injected intraperitonealy CEPO 50 μg/kg,twice a week,while CHF and control group were received the same volume of normal saline at the same time.After four weeks,hemodynamic parameter,Left Ventricular Mass Index(LVMI),the level of serum MMP-2,TIMP-1 and CVF were evaluated respectively.Result:Compared with control group,Left Ventricular Systolic Pressure(LVSP),maximal rate of rise/decline of left ventricular pressure(±dp/dtmax)(P0.01 for each) were significantly decreased,on the other hand,Left ventricular diastolic pressure(LVDP) and Left Ventricular End Diastolic Pressure(LVEDP) were significantly increased(P0.01),the level of serum MMP-2,LVMI and CVF were increased too,but TIMP-1 was decreased(P0.01) in CHF group;Secondly,compared with CHF group,CEPO group have higher LVSP,±dp/dtmax and level of serum TIMP-1(P0.01),lower LVDP,LVEDP,level of serum MMP-2,LVMI and CVF(P0.01).Conclusion:CEPO could reverse myocardial remodeling,improve cardiac function in rats with CHF through regulate the expression of MMP-2,TIMP 1 and degredate the volume of collagen.

Objective To explore the effect of carbamylated erythropoietin on left ventricular remodeling in rats with chronic heart failure(CHF).Methods 10 of 90 healthy male wistar rats were randomly assigned to control group,the rest received intraperitoneal injections of isoproterenol to establish a model of CHF.After 5 weeks,the survived rats were randomly divided into CHF group and CEPO group.CEPO group was administered intraperitoneal injections of CEPO of 50 μg/kg twice a week for 4 weeks;CHF group and the control group received equivalent saline.After the completion of CEPO injection,hemodynamic,level of BNP,and the ratio of left ventricular weight to body weight(LVW/BW) were measured.Results As compared with the control group,left ventricular end systolic pressure(LVSP),maximal rate of rise/decline of left ventricular pressure(±dp/dtmax) were significantly decreased in CHF group(P<0.05),whereas left ventricular end diastolic pressure(LVEDP),level of BNP and the ratio of left ventricular weight to body weight(LVW/BW) were significantly higher(P<0.05).As compared with CHF group,LVSP and ± dp/dtmax were significantly increased(P<0.05),while LVEDP,level of BNP,and LVW/BW were significantly decreased(P<0.05) in CEPO group.Conclusions CEPO can improve cardiac function in rats with CHF by reducing BNP level and alleviating cardiac remodeling.

促红细胞生成素(Erythropoietin,EPO)除了具有造血活性外,还具有广泛组织保护活性.研究发现促红细胞生成素衍生物-氨甲酰化促红细胞生成素,不表现任何促红细胞生成活性,但却具有广泛组织保护作用.体内许多器官和组织包括心脏都表达促红细胞生成素及其受体,它可以减轻缺血缺氧时心肌细胞的损伤,减少心肌细胞的凋亡和促进新生血管生成.目前,对促红细胞生成素及其衍生物的应用,有可能开辟治疗慢性心血管疾病的新途径.

Objective To observe the value of carbamylated erythropoietin(CEPO) on rats with chronic heart failure(CHF) and its possible mechanism.Methods Ninty Wistar rats were randomly divided into intervention,CHF and control group.Both intervention group and CHF group were established models of CHF by intraperitoneal injection of isoproterenol.The intervention group were received CEPO.After 4 weeks,rats were observed changes in hemodynamics,inducible nitric oxide synthase(iNOS) and superoxide dismutase(SOD).Results Compared with control group,left ventricular systolic pressure(LVSP) and maximal rate of rise/decline of left ventricular pressure(±dp/dtmax) were lower(P0.05),whereas left ventricular end-diastolic pressure(LVEDP) and heart rate(HR) were higher(P0.05),the level of iNOS increased(P0.05),the level of SOD decreased(P0.05) in both CHF group and intervention group.Compared with CHF group,intervention group had higher LVSP,±dp/dtmax and SOD levels(P0.05),lower LVEDP,HR and iNOS levels(P0.05).Conclusion CEPO has the role of against CHF by inhibiting the excessive release of nitric oxide and scavenging oxygen free radicals.

动脉粥样硬化(atherosclerosis,AS)是临床常见的一种心血管疾病,是人类最常见的死亡原因之一.近年来研究显示,高同型半胱氨酸(Hcy)血症是造成AS的独立的危险因素,但是其致动脉粥样硬化的作用机制不十分明确[1-2].

Objective To investigate the cardioprotective effects of carbamylated erythropoietin(CEPO) in rats with chronic heart failure(CHF) and its possible mechanism.Methods Ten rats were randomly selected from 90 male Wistar rats as control group,and the rest of the Wistar rats were treated by intraperitoneal injection of isoproterenol(ISO) to establish animal models of CHF.After being fed for 5 weeks,the rats were redivided into CEPO group and CHF group.The CEPO group underwent intraperitoneal injection of CEPO(50μg/kg) twice a week for 4 weeks.The CHF group and control group received equivalent amount of saline at the same time.After 4 weeks of CEPO therapy,the hemodynamics,tumor necrosis-alpha(TNF-α) level and interlerkin-6(IL-6) level in serum,and cardiomyocyte apoptosis rate were measured.Results Compared with the control group,the left ventricular systolic pressure(LVSP) and maximum rate of rise/decline of left ventricular pressure(dp/dtmax) decreased significantly in the CHF group(P<0.05),but the left ventricular end-diastolic pressure(LVEDP) and heart rate(HR) increased significantly(P<0.05).Compared with the CHF group,the LVSP and dp/dtmax increased significantly in the CEPO group(P<0.05),but the LVEDP and HR decreased significantly(P<0.05).Compared with the control group,the TNF-α level and IL-6 level in serum and cardiomyocyte apoptosis rate increased significantly in the CHF group(TNF-α: 4.01±0.20 vs 8.09±0.09 pg/ml,IL-6: 20.93±1.20 vs 30.26±0.94 pg/ml,cardiomyocyte apoptosis rate: 3.80±0.57% vs 22.35±0.60%)(P<0.05).Compared with the CHF group,the TNF-α level and IL-6 level in serum and cardiomyocyte apoptosis rate decreased significantly in the CEPO group(TNF-α: 8.09±0.09 pg/ml vs 6.40±0.14 pg/ml,IL-6: 30.26±0.94 pg/ml vs 25.66±0.74 pg/ml,cardiomyocyte apoptosis rate: 22.35±0.60% vs 13.67±0.36%)(P<0.05).Conclusion CEPO can improve cardiac function in rats with CHF,possibly due to its effects of reducing local inflammation reaction and inhibiting the apoptosis of cardiomyocytes.