非他汀类抗动脉粥样硬化药物治疗研究进展

心血管疾病是现代社会严重威胁人类健康,引起死亡的主要疾病。其中,冠状动脉粥样硬化性心脏病(coronary atherosclerosis heart disease, CAD)占90%以上。心血管疾病已经成为我国医疗保健系统的沉重负担。目前,临床上治疗多应用3羟甲基戊二酰辅酶A(HMG-CoA)还原酶抑制剂(他汀类药物)来抗动脉粥样硬化。本综述通过对目前动脉粥样硬化形成机制研究的介绍,阐述抗动脉粥样硬化研究的基本方向。分析目前他汀类药物抗动脉粥样硬化的机制及研究进展。     

Effects of simvastatin on early oxidative stress and endothelial function in apolipoprotein E-deficient mice

Objective:To investigate the mechanisms that Simvastatin,a 3-ydroxy-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 signiticant 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.     

普伐他丁、维生素E、卡托普利对家兔高脂血症、动脉粥样硬化和脂肪肝形成的影响

目的：寻找能兼顾防治高脂血症、动脉粥样硬化和脂肪肝的有效药物。方法：观察普伐他丁、维生素Ｅ、卡托普利对家兔高脂血症、动脉粥样硬化和脂肪肝形成的影响。结果：普伐他丁可显著降低血脂和改善动脉粥样硬化病变，并有抗脂肪肝作用，联用维生素Ｅ可减轻其潜在的肝毒性；卡托普利有一定的抗动脉粥样硬化作用，且不影响血脂和肝脂质代谢。结论：普伐他丁联用维生素Ｅ、卡托普利可安全用于高脂血症、动脉粥样硬化和脂肪肝患者的治疗     

人类巨细胞病毒感染对血管平滑肌细胞脂代谢相关基因表达的影响

目的研究人类巨细胞病毒感染对体外培养血管平滑肌细胞脂代谢相关基因表达的影响,探讨该病毒致动脉粥样硬化(As)的机制。方法以1 MOI人类巨细胞病毒感染体外培养的血管平滑肌细胞,利用基因表达谱芯片技术检测细胞脂代谢相关基因的表达变化。结果人类巨细胞病毒感染血管平滑肌细胞后,细胞内与脂代谢有关的基因表达出现明显的异常,其中表达上调的基因主要有低密度脂蛋白受体相关蛋白10、11、12、极低密度脂蛋白受体、B型清道夫受体、HMG-CoA合成酶、HMG-CoA还原酶、酰基辅酶A∶胆固醇酰基转移酶及脂肪酶合成酶等基因;表达下调的主要有载脂蛋白A1、载脂蛋白M和载脂蛋白H等基因。结论人类巨细胞病毒感染可能通过改变血管平滑肌细胞脂代谢相关基因的表达而参与As的发病过程。     

Effects of Simvastatin on adiponectin and endothelial function in apolipoprotein E-deficient mice

Objective:To investigate the effects of simvastatin,a 3-hydroxy-3-methylglutaryl coenzyme A(HMG-CoA) reductase inhibitor,on adiponectin and markers of endothelial function in apolipoprotein E-deficient mice at an 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 salin...     

他汀类药物防治帕金森病的临床效果及作用机制研究进展

他汀类药物是一类降血脂药,它们是羟甲基戊二酸单酰辅酶A还原酶的抑制剂。他汀类药物具有多效性,最近的研究表明其可能具有防治帕金森病的潜力。本文就近年来他汀类药物在防治帕金森病的临床效果及作用机制方面的研究进展作一综述。     

普罗布考对颈动脉硬化症的抗氧化和抗炎症作用

目的:观察口服普罗布考对颈动脉硬化症患者氧化低密度脂蛋白(ox-LDL)及血清炎性指标水平的变化,探讨普罗布考对颈动脉硬化症的抗氧化、抗炎症作用。方法:将72例颈动脉硬化症患者随机分为两组:普罗布考组38例,在常规药物治疗的基础上口服普罗布考片0.5g,2次/d,持续12周;对照组34例,常规药物治疗,不服用任何调脂药物及抗氧化剂。分别于治疗前后检测血清ox-LDL、高敏C反应蛋白(hs-CRP)、白细胞介素-lβ(IL-lβ)、基质金属蛋白酶-9(MMP-9)水平及血脂系列等。结果:普罗布考组治疗后总胆固醇(TC)、低密度脂蛋白胆固醇(LDL-C)、ox-LDL、hs-CRP、IL-lβ、MMP-9显著下降(P<0.05);对照组治疗后上述指标均无显著变化。治疗后两组间TC、LDL-C、ox-LDL、hs-CRP、IL-lβ、MMP-9差异有统计学意义(P<0.05)。结论:普罗布考可降低颈动脉硬化症患者的TC、LDL-C、ox-LDL、hs-CRP、IL-lβ和MMP-9水平,并具有一定程度的抗氧化和抑制动脉粥样硬化慢性炎症过程的作用。     

Effects of Simvastatin on adiponectin and endothelial function in apolipoprotein E–deficient mice

学长辅导计划是近年来高校学生管理部门?学生思政工作者共同探索?推出的大学生教育管理的有效模式?本文探讨了学长辅导计划的由来和意义,通过有目的地遴选培训一批高年级优秀学长,发挥学长对低年级学生的“传?帮?带”作用,鼓励学长们主动积极地去辅导低年级学生,帮助他们更快适应大学生活,顺利完成高中到大学的转变,融入到大学生活中去,使学校的教育管理模式得以创新,从而落实学长辅导制度,凸显辅导成效?     

心肌桥Noble分级和发生位置与冠状动脉粥样硬化的关系

目的 探讨心肌桥Noble分级和发生位置与冠状动脉粥样硬化的关系。 方法 回顾性分析经冠状动脉造影检查出的192例心肌桥患者,结合临床症状以及心电图和心脏超声表现,分析心肌桥Noble分级和发生位置与冠状动脉粥样硬化的关系及药物治疗效果。 结果 心肌桥在冠状动脉造影的检出率为10.2%,最常发生在左前降支中段;Noble 3级患者均出现胸闷或胸痛症状,43.8%出现心电图缺血性ST-T改变,37.5%出现心脏超声室壁节段运动异常,Noble 1、2级患者不出现心电图缺血性ST-T改变和心脏超声室壁节段运动异常;心肌桥近端冠状动狭窄发生率显著高于壁冠状动脉及其远端冠状动脉（P<0.05）;随着心肌桥分级的增高,心肌桥近端冠状动脉狭窄的发生率有增高的趋势（P<0.000 1）;有症状的心肌桥患者β受体阻滞剂、钙离子拮抗剂、β受体阻滞剂联合钙离子拮抗剂使用率分别为80.0%、91.1%和62.2%,显著高于无症状者的11.4%、15.9%、4.5%（P<0.01）。 结论 冠状动脉心肌桥Noble 3级患者大多出现胸闷或胸痛症状;心肌桥近端较易发生冠状动脉粥样硬化;以β受体阻滞剂和钙离子拮抗剂治疗为主。     

支架成形术治疗动脉粥样硬化性进展性脑梗死的疗效观察

目的 评价支架成形术（SAA）治疗动脉粥样硬化性进展性脑梗死的临床疗效及安全性。方法 选择40例急性大动脉粥样硬化性缺血性进展性脑梗死患者,配对分为SAA组（n=20）与药物治疗组（n=20）。药物治疗组给予阿司匹林、氯吡格雷、他汀类、降压药等常规治疗;SAA组则在常规治疗的基础上进行数字减影血管造影检查,对高度狭窄或伴不稳定斑块的主干动脉予以球囊扩张和SAA治疗。观察两组患者入组时、发病后第21天的美国国立卫生院神经功能缺损（NIHSS）评分、治疗后第90天的改良Rankin 量表（mRS）评分;记录治疗过程中出现的不良事件。结果 发病后第21天,SAA组NIHSS评分明显低于药物治疗组,差异有统计学意义（P<0.001）。SAA组与药物治疗组mRS评分为0～1分的患者分别为16例和6例,差异有统计学意义（P=0.001）。药物治疗组有1例患者再发脑梗死,SAA组无复发病例。结论 SAA是动脉粥样硬化性进展性脑梗死的有效干预措施。     

动脉粥样硬化的防治

动脉粥样硬化是心血管系统最常见的疾病,也是危害人类健康的常见病。随着分子生物学和病理生理学的发展,现已揭示动脉粥样硬化是一个可以被改善的动态过程。近年来在抗动脉粥样硬化方面,随着循证医学不断证明他汀类调脂药在抗动脉粥样硬化的确切作用及基因治疗的发展,抗动脉粥样硬化防治有了飞速发展,本文从药物及基因等方面简述动脉粥样硬化的防治。     

脂联素与临床疾病的关系及其治疗

脂联素由脂肪细胞分泌,是一种具有多种生物效应的细胞因子。脂联素通过与其受体结合,调节糖代谢、脂代谢、炎性反应、胰岛素抵抗及动脉粥样硬化等。心血管药物和胰岛素增敏剂等药物通过增加脂联素而改善胰岛素抵抗、降低炎性反应、减少糖尿病肾病白蛋白尿、抗动脉粥样硬化等。现就脂联素与临床疾病的关系及抗高血压药、抗血小板药、抗糖尿病药等对脂联素的影响进行综述。     

他汀类药物抗肿瘤作用的研究进展

他汀类药物(Statins)作为羟甲基戊二酸单酰辅酶A(HMG-CoA)还原酶抑制剂,已普遍用于临床治疗高脂血症。HMG-CoA还原酶是细胞内甲羟戊酸合成途径的限速酶,他汀类药物通过抑制其作用,减少甲羟戊酸(MVA)合成及其下游产物,从而影响细胞许多重要的生理学功能:细胞膜构成、糖蛋白合成、细胞内信号转导及细胞周期进展等。近年来,他汀类药物除降血脂作用外,其抑制肿瘤细胞增殖、诱导分化或凋亡、抗侵袭作用及增强放疗方面的作用逐渐被国内外学者认识。     

Policosanol modulates HMG-CoA reductase activity in cultured fibroblasts

BACKGROUND: Cholesterol biosynthesis is strictly controlled by 3-hydroxy-3-methylglutaryl Coenzyme A (HMG-CoA) reductase. METHODS: Transfer of cultured fibroblasts to a lipid-depleted medium (LDM) up-regulates the enzyme levels. This, in turn, is followed by an accelerated biosynthesis of cholesterol. RESULTS: Exposure of Vero fibroblasts to LDM and policosanol (0.5-50 microg/mL), a new cholesterol-lowering drug purified from sugarcane (Saccharum officinarum L.) wax, decreased in a dose-dependent manner cholesterol biosynthesis from [14C]-acetate and 3H-water, but not from [14C]-mevalonate. CONCLUSIONS: This suggests an effect on HMG-CoA reductase, the rate-controlling enzyme in cholesterol biosynthesis. When enzyme activity was measured in the presence of various concentrations of policosanol (0.5-50 microg/mL), reductase was not suppressed. Therefore, there was no evidence for a competitive or noncompetitive inhibition of enzyme activity. However, after treatment of intact cells with policosanol (50 microg/mL) in the presence of LDM, a suppressive effect on enzyme activity was observed, suggesting a modulatory effect of policosanol on reductase activity. The previous inhibition of enzyme up-regulation by policosanol suggests to date a depression of de novo synthesis of HMG-CoA reductase and/or stimulation of its degradation. However, the exact mechanism by which policosanol inhibits the activity of HMG-CoA reductase still remains unclear. Further studies are needed to clarify the precise mechanism of its inhibitory action on cholesterol biosynthesis.     

HMG-CoA reductase inhibitors and the risk of fractures

CONTEXT: Recent animal studies have suggested that 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) increase bone formation, volume, and density. It is unknown whether use of statins is associated with a decreased risk of fractures in humans. OBJECTIVE: To determine whether exposure to statins, fibrates, or other lipid-lowering drugs is associated with reduced bone fracture risk. DESIGN: Population-based, nested case-control analysis. SETTING: The UK-based General Practice Research Database (GPRD), comprising some 300 practices, with data collection from the late 1980s until September 1998. SUBJECTS: Within a base population of 91,611 individuals aged at least 50 years (28,340 individuals taking lipid-lowering drugs, 13,271 untreated individuals with a diagnosis of hyperlipidemia, and 50,000 randomly selected individuals without diagnosis of hyperlipidemia), we identified 3940 case patients who had a bone fracture and 23,379 control patients matched for age (+/-5 years), sex, general practice attended, calendar year, and years since enrollment in the GPRD. MAIN OUTCOME MEASURES: Use of statins, fibrates, or other lipid-lowering drugs in case patients vs control patients. RESULTS: After controlling for body mass index, smoking, number of physician visits, and corticosteroid and estrogen use, current use of statins was associated with a significantly reduced fracture risk (adjusted odds ratio [OR], 0.55; 95% confidence interval [CI], 0.44-0.69) compared with nonuse of lipid-lowering drugs. Current use of fibrates or other lipid-lowering drugs was not related to a significantly decreased bone fracture risk (adjusted OR, 0.87; 95% CI, 0.70-1.08 and adjusted OR, 0.76; 95% CI, 0.41-1.39, respectively). CONCLUSIONS: This study suggests that current exposure to statins is associated with a decreased risk of bone fractures in individuals age 50 years and older. This finding has a potentially important public health impact and should be confirmed further in controlled prospective trials. JAMA. 2000;283:3205-3210     

3-羟-3甲基戊二酰辅酶A还原酶基因多态与血浆高浓度低密度脂蛋白的风险

目的:研究潮汕人群3-羟-3甲基戊二酰辅酶A(HMG-CoA)还原酶基因多态性与血浆高浓度低密度脂蛋白(LDL)的风险.方法:收集潮汕籍汉族高浓度LDL 792例,并与1 073名健康人对照,用SNPstream技术检测样本HMG-CoA还原酶基因多态性.结果:2个单核苷酸多态性位点(rs3846662和rs12916)与高浓度LDL均有相关性(P＜0.05),2个单倍型G-T-C和A-C-C在两组中的分布差异有统计学意义(P＜0.05).结论:HMG-CoA还原酶2个单核苷酸多态性和2个单倍型均与血浆高浓度低密度脂蛋白LDL存在相关性.     

胰岛素抵抗及2型糖尿病对原发性高血压患者血压昼夜节律及动脉硬化的影响

目的 研究原发性高血压(EH)、EH合并胰岛素抵抗(IR)及EH合并2型糖尿病(T2DM)对患者血压昼夜节律及动脉血管硬化的影响.方法 选取2015年1月至2017年1月四川省人民医院E H患者150例,按是否合并IR及T2DM,分为对照组、IR组及T2DM组,每组各50例.治疗后,通过比较3组间血压昼夜节律及其变异性和检测颈动脉硬化检出率,以有无颈动脉硬化为因变量,进行Logistic回归分析.结果 T2DM组首诊3月后,24 h收缩压和舒张压、24 h收缩压标准差、24 h收缩压和舒张压变异系数、白昼收缩压和舒张压、夜间收缩压和舒张压、非杓型节律的比例及颈动脉硬化检出率均高于IR组和对照组(P<0.05),且T2DM组夜间收缩压和舒张压下降百分率均较IR组及对照组明显降低(P<0.05).IR组首诊3月后,24 h收缩压、24 h收缩压和舒张压标准差、24 h收缩压变异系数、白昼收缩压及夜间舒张压均高于对照组(P<0.05),夜间收缩压和舒张压下降百分率较对照组明显降低(P<0.05).Logistic回归分析显示,T2DM是颈动脉硬化的危险因素(OR=2.175),夜间舒张压下降率是颈动脉硬化的保护因素(OR=0.913).结论 EH患者合并T2DM或IR均能够明显增加血压昼夜节律异常的发生,T2DM是EH患者发生颈动脉硬化的独立危险因素.     

HMG-CoA还原酶抑制剂对X综合征血管内皮功能的影响

目的 :通过应用HMG -CoA还原酶抑制剂 (普伐他汀 )对x综合浆内征患者的血管内皮功能的影响 ,观察微血管病变引起的心肌缺血的改善作用。方法 :严格筛选 17例临床表现为胸痛并已作冠脉造影正常的患者服用普伐他汀 10mg。每晚睡前服 1次 ,疗程 3个月 ,用药前后进行血浆内皮素 (ET)的检测及活动平板运动试验 ,比较用药前后各项指标的变化情况。结果 :血浆ET水平较治疗前明显降低 (P <0 .0 1) ,运动出现心绞痛ST段改变的时间明显延长 (P <0 .0 5 ) ;ST段恢复时间显著缩短 (P <0 .0 5 )运动后 4分时相各导联运动诱发的ST段缺血型下降之和 (∑ST)明显减少。结论 :HMG -CoA还原酶抑制剂 (普伐他汀 )可显著改善X综合征患者的血管内皮功能异常 ,减轻心肌缺血 ,对X综合征有治疗作用     

Expression,Purification,Characteristics and Homology Modeling of the HMGS from Streptococcus pneumoniae

Objective To understand the molecular basis for a potential reaction mechanism and develop novel antibiotics with homology modeling for 3-hydroxy-3-methylglutaryl coenzyme A （HMG-CoA） synthase （HMGS）. Methods The genetic engineering technology and the composer module of SYBYL7.0 program were used, while the HMGS three-dimensional structure was analyzed by homology modeling. Results The mvaS gene was cloned from Streptococcus pneumoniae and overexpressed in Escherichia coli from a pET28 vector. The expressed enzyme （about 46 kDa） was purified by affinity chromatography with a specific activity of 3.24 μmol/min/mg. Optimal conditions were pH 9.75 and 10 mmol/L MgCl2 at 37 ℃ The Vmax and Km were 4.69 μmol/min/mg and 213 μmol/L respectively. The 3D model of S.pneumoniae HMGS was established based on structure template of HMGS of Enterococcus faecalis. Conelusion The structure of HMGS will facilitate the structure-based design of alternative drugs to cholesterol-lowering therapies or to novel antibiotics to the Gram-positive cocci, whereas the recombinant HMGS will prove useful for drug development against a different enzyme in the mevalonate pathway.