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
目的探讨高热量饮食和年龄对载脂蛋白E基因敲除(ApoE^(-/-))小鼠脑功能的影响。方法选取8月龄成年ApoE^(-/-)小鼠和18月龄老年ApoE^(-/-)小鼠共20只,随机分为正常饮食成年组、正常饮食老年组、高热量饮食成年组、高热量饮食老年组,每组...目的探讨高热量饮食和年龄对载脂蛋白E基因敲除(ApoE^(-/-))小鼠脑功能的影响。方法选取8月龄成年ApoE^(-/-)小鼠和18月龄老年ApoE^(-/-)小鼠共20只,随机分为正常饮食成年组、正常饮食老年组、高热量饮食成年组、高热量饮食老年组,每组5只。正常饮食成年组、正常饮食老年组小鼠喂食实验室标准饲料,高热量饮食成年组、高热量饮食老年组小鼠喂食高脂饲料,干预8周。用体质量监测和葡萄糖耐量实验测试小鼠体质量、血糖变化,核磁共振波谱检测海马和下丘脑N-乙酰天冬氨酸(NAA)、胆碱(Cho)含量,Y迷宫和旷场实验检测认知功能,Western blot检测脑组织突触体相关蛋白25(SNAP-25)、突触素(synaptophysin)、突触后致密蛋白95(PSD-95)、诱导型一氧化氮合酶(iNOS)、白细胞介素1β(IL-1β)表达。结果与正常饮食成年组比较,高热量饮食成年组海马NAA、下丘脑Cho和NAA、自发交替率、SNAP-25、synaptophysin、PSD-95表达降低,差异有统计学意义(P<0.05,P<0.01),iNOS、IL-1β表达升高,差异有统计学意义(P<0.01);与正常饮食成年组比较,正常饮食老年组海马NAA、下丘脑Cho、SNAP-25、synaptophysin、PSD-95表达降低(P<0.05,P<0.01),iNOS、IL-1β表达升高(P<0.01);与正常饮食老年组比较,高热量饮食老年组海马和下丘脑Cho和NAA、中心路程/总路程、SNAP-25、synaptophysin、PSD-95表达降低(P<0.05,P<0.01),iNOS、IL-1β表达升高(P<0.01);与高热量饮食成年组比较,高热量饮食老年组海马NAA、中心路程/总路程、平均速度、synaptophysin表达降低(P<0.05,P<0.01),iNOS、IL-1β表达升高(1.61±0.10 vs 1.35±0.13,2.04±0.08 vs 1.54±0.11,P<0.05,P<0.01)。结论高热量饮食导致ApoE^(-/-)小鼠代谢障碍和神经炎症,抑制突触蛋白表达引起认知功能障碍;长期高热量饮食和年龄增加促进ApoE^(-/-)小鼠脑功能衰退。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.
文摘目的探讨高热量饮食和年龄对载脂蛋白E基因敲除(ApoE^(-/-))小鼠脑功能的影响。方法选取8月龄成年ApoE^(-/-)小鼠和18月龄老年ApoE^(-/-)小鼠共20只,随机分为正常饮食成年组、正常饮食老年组、高热量饮食成年组、高热量饮食老年组,每组5只。正常饮食成年组、正常饮食老年组小鼠喂食实验室标准饲料,高热量饮食成年组、高热量饮食老年组小鼠喂食高脂饲料,干预8周。用体质量监测和葡萄糖耐量实验测试小鼠体质量、血糖变化,核磁共振波谱检测海马和下丘脑N-乙酰天冬氨酸(NAA)、胆碱(Cho)含量,Y迷宫和旷场实验检测认知功能,Western blot检测脑组织突触体相关蛋白25(SNAP-25)、突触素(synaptophysin)、突触后致密蛋白95(PSD-95)、诱导型一氧化氮合酶(iNOS)、白细胞介素1β(IL-1β)表达。结果与正常饮食成年组比较,高热量饮食成年组海马NAA、下丘脑Cho和NAA、自发交替率、SNAP-25、synaptophysin、PSD-95表达降低,差异有统计学意义(P<0.05,P<0.01),iNOS、IL-1β表达升高,差异有统计学意义(P<0.01);与正常饮食成年组比较,正常饮食老年组海马NAA、下丘脑Cho、SNAP-25、synaptophysin、PSD-95表达降低(P<0.05,P<0.01),iNOS、IL-1β表达升高(P<0.01);与正常饮食老年组比较,高热量饮食老年组海马和下丘脑Cho和NAA、中心路程/总路程、SNAP-25、synaptophysin、PSD-95表达降低(P<0.05,P<0.01),iNOS、IL-1β表达升高(P<0.01);与高热量饮食成年组比较,高热量饮食老年组海马NAA、中心路程/总路程、平均速度、synaptophysin表达降低(P<0.05,P<0.01),iNOS、IL-1β表达升高(1.61±0.10 vs 1.35±0.13,2.04±0.08 vs 1.54±0.11,P<0.05,P<0.01)。结论高热量饮食导致ApoE^(-/-)小鼠代谢障碍和神经炎症,抑制突触蛋白表达引起认知功能障碍;长期高热量饮食和年龄增加促进ApoE^(-/-)小鼠脑功能衰退。
