Objective： To investigate the mechanisms that Simvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A（HMG-CoA） reductase inhibitor, plays an important role in primary prevention of atherosclerosis independently of its...Objective： To investigate the mechanisms that Simvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A（HMG-CoA） reductase inhibitor, plays an important role in primary prevention of atherosclerosis independently of its lipid-lowering effect in Apolipoprotein E-deficient mice in the early stage of atherosclerosis. Methods： Twenty-four 6-week old male apoE-deficient mice were randomly divided into two groups：control group（normal saline） and treatment group[simvastatin（5 mg/（kg · d））]. Simvastatin was administered to treatment group mice by gavage and the same volume of normal saline was administered to control group mice by the same method for 2 or 4 weeks. Total cholesterol（TC）, super-oxide dismutase（SOD）, malondialdehyde（MDA） and serum nitric oxide（NO） were measured by biochemical analysis. Results： There was no significant difference in serum TC between control and treatment groups. Compared with the control＇ s, the effects of simvastatin were more significant in decreasing serum MDA level（P 〈 0.01 vs control＇ s at 2-week; P 〈 0.006 vs control＇ s at 4-week）, increasing serum SOD level（P 〈 0.03 vs control＇ s at 2-week; P 〈 0.003 vs control＇ s at 4-week） and NO level （P 〈 0.01 control＇ s at 2-week; P 〈 0.001 vs control＇ s at 4-week） either at 2 or 4 weeks. Conclusion： Simvastatin attenuates oxidative stress and protects endothelial function by the mechanisms of decreasing serum MDA level, increasing serum SOD level and NO level, which were inconsistent with its cholesterol-lowering effect. It may play an important role in primary（if not all） prevention of atherosclerosis and might be independent of lipid-regulation mechanism.展开更多
Background Restenosis and atherosclerosis are two disorders characterized by abundant proliferation and migration of vascular smooth muscle cells(VSMCs).Previous studies have demonstrated a protective effect of the ce...Background Restenosis and atherosclerosis are two disorders characterized by abundant proliferation and migration of vascular smooth muscle cells(VSMCs).Previous studies have demonstrated a protective effect of the cellular repressor of E1A-stimulated genes(CREG) against restenosis. However,the role of CREG in atherosclerosis is undetermined. The aim of the present study is to examine the impact of CREG on the atherosclerosis.Methods Both immunofluorescence and western blotting were used in this experiment. Results The expression of CREG was decreased markedly in atherosclerotic lesions compared with normal areas of the vessels from both humans and mice species.We furthermore demonstrated that compared with the adenovirus-mediated-GFP control,intravenous administration of adenovirus-mediated CREG to apolipoprotein E deficient mice with six-week high-fat diet significantly reduced the relative area of atherosclerotic lesions in the mice aorta,accompanied by a decreased levels of Tumor necrosis factor(TNF) -αand Interleukin (IL)-1βmeasured by ELISA.Meanwhile,Western analysis revealed that NF-κB activation was also markedly reduced.Studies of cultured human VSMCs identified that overexpression of CREG abrogated the proliferation of human VSMCs stimulated by ox-LDL,along with a significantly decreased releasing of TNF-αand IL-1β.Conversely,down-regulation CREG expression contributed to cells proliferation stimulated by ox-LDL in cultured human VSMCs.Furthermore, overexpression of CREG suppressed the activations of NF-kB and ERK1/2 in cultured cells,while Furthermore, treatment with ERK inhibitor PD98059 reversed the CREG-mediated inhibition of human VSMCs proliferation.Conclusions CREG has a protective effect against atherosclerosis, which is related to inhibiting proliferation and inflammatory response of VSMCs.展开更多
目的研究C1q/肿瘤坏死因子相关蛋白9(CTRP9)对高脂血症模型载脂蛋白E基因敲除(ApoE^(-/-))小鼠肝脏脂肪病变形成的影响及机制。方法将30只8周龄雄性ApoE^(-/-)小鼠随机分为对照组与观察组,每组15只,对照组小鼠给予尾静脉注射腺病毒空载...目的研究C1q/肿瘤坏死因子相关蛋白9(CTRP9)对高脂血症模型载脂蛋白E基因敲除(ApoE^(-/-))小鼠肝脏脂肪病变形成的影响及机制。方法将30只8周龄雄性ApoE^(-/-)小鼠随机分为对照组与观察组,每组15只,对照组小鼠给予尾静脉注射腺病毒空载绿色荧光蛋白(Ad-GFP),观察组小鼠给予尾静脉注射腺病毒载CTRP9(Ad-CTRP9),高脂高胆固醇饮食(HF/HC)饲喂12周后,采集尾静脉血,处死小鼠收集肝脏组织。采用HE、油红O染色观察CTRP9对ApoE^(-/-)小鼠肝脏脂肪病变形成的影响;采用real time PCR检测CTRP9及脂质合成、炎症相关和线粒体氧化磷酸化相关基因的表达水平;采用western blotting技术检测肝脏组织中CTRP9蛋白表达水平。结果与对照组相比,过表达CTRP9小鼠(观察组)体重和血脂水平差异无统计学意义(P>0.05),CTRP9基因和蛋白表达水平显著升高(P<0.05),肝脏脂肪病变显著减少(P<0.05),肝脏组织中甘油三酯和总胆固醇水平显著下降(P<0.05),脂质合成(FAS、SCD1、SREBP1c)以及炎症相关基因(MCP-1、MIP1α和IL-1β)表达水平显著下调(P<0.01或P<0.001),而脂质代谢(PPARα、PPARγ、LXRα和LXRβ)及线粒体氧化磷酸化相关基因(CPT1、CPT2、COX4、Cytoc、Acadl和Acadm)表达水平显著增加(P<0.05或P<0.01)。结论过表达CTRP9能够抑制肝脏组织中脂肪生成以及炎症反应,同时促进肝细胞脂肪酸氧化磷酸化和能量代谢,增加线粒体能量消耗,从而降低肝脏组织中脂质蓄积。展开更多
基金This study was supported by Provincial Natural Science Foundation of the Department of Education of Jiangsu(01 KJB320003)Innova-tion Fund of Nanjiing Medical University(CX 003001)
文摘Objective： To investigate the mechanisms that Simvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A（HMG-CoA） reductase inhibitor, plays an important role in primary prevention of atherosclerosis independently of its lipid-lowering effect in Apolipoprotein E-deficient mice in the early stage of atherosclerosis. Methods： Twenty-four 6-week old male apoE-deficient mice were randomly divided into two groups：control group（normal saline） and treatment group[simvastatin（5 mg/（kg · d））]. Simvastatin was administered to treatment group mice by gavage and the same volume of normal saline was administered to control group mice by the same method for 2 or 4 weeks. Total cholesterol（TC）, super-oxide dismutase（SOD）, malondialdehyde（MDA） and serum nitric oxide（NO） were measured by biochemical analysis. Results： There was no significant difference in serum TC between control and treatment groups. Compared with the control＇ s, the effects of simvastatin were more significant in decreasing serum MDA level（P 〈 0.01 vs control＇ s at 2-week; P 〈 0.006 vs control＇ s at 4-week）, increasing serum SOD level（P 〈 0.03 vs control＇ s at 2-week; P 〈 0.003 vs control＇ s at 4-week） and NO level （P 〈 0.01 control＇ s at 2-week; P 〈 0.001 vs control＇ s at 4-week） either at 2 or 4 weeks. Conclusion： Simvastatin attenuates oxidative stress and protects endothelial function by the mechanisms of decreasing serum MDA level, increasing serum SOD level and NO level, which were inconsistent with its cholesterol-lowering effect. It may play an important role in primary（if not all） prevention of atherosclerosis and might be independent of lipid-regulation mechanism.
文摘Background Restenosis and atherosclerosis are two disorders characterized by abundant proliferation and migration of vascular smooth muscle cells(VSMCs).Previous studies have demonstrated a protective effect of the cellular repressor of E1A-stimulated genes(CREG) against restenosis. However,the role of CREG in atherosclerosis is undetermined. The aim of the present study is to examine the impact of CREG on the atherosclerosis.Methods Both immunofluorescence and western blotting were used in this experiment. Results The expression of CREG was decreased markedly in atherosclerotic lesions compared with normal areas of the vessels from both humans and mice species.We furthermore demonstrated that compared with the adenovirus-mediated-GFP control,intravenous administration of adenovirus-mediated CREG to apolipoprotein E deficient mice with six-week high-fat diet significantly reduced the relative area of atherosclerotic lesions in the mice aorta,accompanied by a decreased levels of Tumor necrosis factor(TNF) -αand Interleukin (IL)-1βmeasured by ELISA.Meanwhile,Western analysis revealed that NF-κB activation was also markedly reduced.Studies of cultured human VSMCs identified that overexpression of CREG abrogated the proliferation of human VSMCs stimulated by ox-LDL,along with a significantly decreased releasing of TNF-αand IL-1β.Conversely,down-regulation CREG expression contributed to cells proliferation stimulated by ox-LDL in cultured human VSMCs.Furthermore, overexpression of CREG suppressed the activations of NF-kB and ERK1/2 in cultured cells,while Furthermore, treatment with ERK inhibitor PD98059 reversed the CREG-mediated inhibition of human VSMCs proliferation.Conclusions CREG has a protective effect against atherosclerosis, which is related to inhibiting proliferation and inflammatory response of VSMCs.
文摘目的研究C1q/肿瘤坏死因子相关蛋白9(CTRP9)对高脂血症模型载脂蛋白E基因敲除(ApoE^(-/-))小鼠肝脏脂肪病变形成的影响及机制。方法将30只8周龄雄性ApoE^(-/-)小鼠随机分为对照组与观察组,每组15只,对照组小鼠给予尾静脉注射腺病毒空载绿色荧光蛋白(Ad-GFP),观察组小鼠给予尾静脉注射腺病毒载CTRP9(Ad-CTRP9),高脂高胆固醇饮食(HF/HC)饲喂12周后,采集尾静脉血,处死小鼠收集肝脏组织。采用HE、油红O染色观察CTRP9对ApoE^(-/-)小鼠肝脏脂肪病变形成的影响;采用real time PCR检测CTRP9及脂质合成、炎症相关和线粒体氧化磷酸化相关基因的表达水平;采用western blotting技术检测肝脏组织中CTRP9蛋白表达水平。结果与对照组相比,过表达CTRP9小鼠(观察组)体重和血脂水平差异无统计学意义(P>0.05),CTRP9基因和蛋白表达水平显著升高(P<0.05),肝脏脂肪病变显著减少(P<0.05),肝脏组织中甘油三酯和总胆固醇水平显著下降(P<0.05),脂质合成(FAS、SCD1、SREBP1c)以及炎症相关基因(MCP-1、MIP1α和IL-1β)表达水平显著下调(P<0.01或P<0.001),而脂质代谢(PPARα、PPARγ、LXRα和LXRβ)及线粒体氧化磷酸化相关基因(CPT1、CPT2、COX4、Cytoc、Acadl和Acadm)表达水平显著增加(P<0.05或P<0.01)。结论过表达CTRP9能够抑制肝脏组织中脂肪生成以及炎症反应,同时促进肝细胞脂肪酸氧化磷酸化和能量代谢,增加线粒体能量消耗,从而降低肝脏组织中脂质蓄积。
