罗格列酮的抗氧化功能及其机制的实验研究

目的:观察罗格列酮对动脉粥样硬化兔高密度脂蛋白(HDL)亚组分结构与抗氧化功能的影响,并进一步探讨罗格列酮抗动脉粥样硬化的机制。方法:18只新西兰大白兔随机分为:①正常对照组(n=6):给予普通饮食喂养;②动脉粥样硬化组(n=6):饲以高脂饲料;③罗格列酮组(n=6):在饲以高脂饲料基础上予以灌服罗格列酮0.5 mg/(kg.d)。喂养12周后取血,以酶法测定血脂;分光光度计法测量血清屏氧酶1活性;化学沉淀法测定HDL亚组分的比例;将主动脉常规苏木素-伊红(Hema-toxylin-eosin,HE)染色进行组织病理学观察。结果:实验12周后,与动脉粥样硬化组相比,罗格列酮组血清高密度脂蛋白胆固醇(HDL-C)水平显著升高(P=0.001);屏氧酶1活性显著升高(P=0.000);HDL2/HDL比例明显升高(P=0.000),主动脉内中膜厚度明显减少(P=0.000),斑块面积/血管腔面积比值显著下降(P=0.002),差异均有统计学意义。结论:罗格列酮能升高血清HDL-C水平,增加HDL2/HDL比例,升高血清PON1活性,减少主动脉内中膜厚度及斑块面积/血管腔面积比值,改善了HDL功能,具有减少动脉粥样硬化斑块作用。     

L-4F对载脂蛋白E缺失小鼠高密度脂蛋白抗炎抗氧化功能的影响

目的观察载脂蛋白A-Ⅰ(apoA-Ⅰ)模拟肽L-4F对高脂喂养apoE缺失小鼠HDL抗炎、抗氧化功能的影响,探讨L-4F的抗动脉粥样硬化(AS)机制。方法 8周龄C57BL/6J小鼠18只,普通饲料喂养作为对照组;8周龄apoE缺失小鼠30只,高脂饲料喂养,喂养4周后,随机处死2种小鼠各6只,检测相应指标作为研究基线(第4周)。其余apoE缺失小鼠随机分为AS组和L-4F组[L-4F1mg/(kg.d)腹腔注射)],每组12只。实验第8、16周末取标本测定血脂水平、血清对氧磷酯酶1(PON1)、髓过氧化物酶(MPO)活性、高敏C反应蛋白(hs-CRP)含量及HDL炎症指数(HII),观察主动脉斑块面积。结果实验16周后,与AS组比较,L-4F组血脂水平无明显变化,血清PON1活性明显升高,MPO活性、hs-CRP、HII显著下降,主动脉斑块/血管内膜表面积比值明显减小(P<0.05,P<0.01)。结论 L-4F可通过升高PON1活性、降低MPO活性,抑制炎性反应、降低HII等,改善HDL抗炎抗氧化功能,从而减少主动脉内中膜厚度和斑块面积,发挥抗AS作用。     

普罗布考对高脂喂养LDLR-/-小鼠动脉粥样硬化的影响及机制研究

目的探讨普罗布考对高脂喂养LDLR-/-小鼠动脉粥样硬化的影响并初步阐明其作用机制。方法14只8周龄LDLR-/-雄性小鼠,予以高脂喂养4周后随机分为高脂组（继续高脂饮食,n=7）和普罗布考组（高脂加0．5％普罗布考,n=7）,喂养14周后处死,检测血浆中甘油三酯（TG）、总胆固醇（TG）和高密度脂蛋白胆固醇（HDL—C）水平;取主动脉进行油红0染色观察斑块生长情况;制作主动脉根部冰冻切片,分别进行油红0、Masson染色,检测主动脉根部斑块面积和胶原含量;ELISA检测血浆中炎症因子IL-12p70水平。结果普罗布考组小鼠血浆TG、HDL—C显著低于高脂组（P均〈0．01）,TG无显著改变（P〉0．05）;油红O染色结果显示,两组间主动脉斑块占主动脉比例无显著差异（P〉0．05）,但普罗布考组小鼠主动脉根部斑块面积显著高于高脂组（P〈0．01）;Masson染色结果显示,普罗布考组小鼠主动脉根部斑块中胶原比例显著高于高脂组（P〈0．01）;ELISA结果显示,普罗布考组小鼠血浆IL-12p70水平显著低于高脂组（P〈0．05）。结论普罗布考可降低高脂喂养的LDLR-/-小鼠血浆TG、HDL-C和IL-12p70水平,促进主动脉根部斑块形成,但增加主动脉根部斑块中胶原含量。     

普罗布考对兔动脉粥样硬化模型C反应蛋白水平的影响及其与斑块稳定性的关系

目的观察兔动脉粥样硬化(AS)模型中C反应蛋白(CRP)的水平与斑块稳定性之间的关系,及普罗布考对CRP水平的影响。方法 20只新西兰大白兔采用随机数字表法分为正常对照组(n=6)、高脂饮食组(n=8)和普罗布考组(n=6)。对照组予普通饲料喂养,高脂饮食组和普罗布考组予高脂饲料喂养。4周后高脂饮食组和普罗布考组行髂动脉内膜球囊损伤术。术后普罗布考组每只大白兔加用普罗布考1g/d口服,10周末取血测血清CRP水平,之后处死动物取损伤处动脉,用HE染色观察动脉病理形态学变化。结果高脂饮食组动脉可见典型的AS斑块形成,普罗布考组无典型斑块形成,内膜增厚较为明显;与高脂饮食组比较,普罗布考组血清CRP水平较低[(8.10±1.02)mg/L比(11.35±2.32)mg/L,P<0.05]。结论 CRP在兔AS模型的表达水平明显增加,与斑块的不稳定性有关,普罗布考有一定的抑制兔AS模型血清CRP表达的作用。     

普罗布考对动脉粥样硬化兔的高密度脂蛋白逆转运功能中酶蛋白和受体的影响

目的:探讨普罗布考对动脉粥样硬化(AS)兔的高密度脂蛋白逆转运功能中酶蛋白和受体的影响。方法:新西兰大白兔(共24只)随机分为3组:对照组(n=8):用普通饲料饲养;高脂组(n=8):用高脂饲料喂养;普罗布考组(n=8):在高脂饲料的基础上给予普罗布考喂养。饲养12周通过比色法测定血脂,通过酶联免疫吸附法检测血清磷脂胆固醇酰基转移酶(LCAT)和胆固醇酯转移蛋白(CETP),并采用免疫组化方法检测主动脉壁斑块内三磷酸腺苷结合盒转运体A1(ABCA1)和清道夫受体-BI(SR-BI)表达水平。结果:实验后第12周(1)血脂指标:与高脂组比较,普罗布考组血清总胆固醇[TC,(15.95±1.51)mmol/L vs(21.95±3.71)mmol/L]、低密度脂蛋白胆固醇[LDL-C,(13.01±2.28)mmol/L vs(17.90±3.51)mmol/L]、高密度脂蛋白胆固醇[HDL-C,(0.56±0.10)mmol/L vs(1.13±0.12)mmol/L]水平明显下降,差异均有统计学意义(P0.01)。(2)LCAT和CETP:与对照组[CETP(2.07±0.64)μg/ml和LCAT(27.01±8.26)μg/ml]比较,高脂组[CETP(1.24±0.54)μg/ml和LCAT(15.02±3.81)μg/ml]明显降低,差异均有统计学意义(P0.05);与高脂组比较,普罗布考组[CETP(3.43±1.01)μg/ml和LCAT(38.10±7.96)μg/ml]明显升高,差异均有统计学意义(P0.05)。(3)主动脉壁斑块ABCA1和SR-BI受体表达:与高脂组比较,普罗布考组ABCA1阳性表达的面积(%)显著增加[(46.81±10.01)%vs(24.10±8.48)%,P0.01];SR-B1阳性表达面积(%)亦显著增加[(48.04±10.90)%vs(18.61±6.77)%,P0.01],两组比较差异均有统计学意义。结论:普罗布考通过增加高密度脂蛋白外周动脉受体ABCA1和SR-BI表达,增加LCAT和CETP的量,促进HDL的RCT功能,从而改善HDL的功能。     

二氢杨梅素对高脂诱导动脉粥样硬化兔自噬相关蛋白表达的影响

目的:探讨二氢杨梅素对高脂诱导动脉粥样硬化(AS)兔主动脉弓自噬相关蛋白表达的影响,以阐明其抗AS的分子机制。方法:24只健康雄性新西兰兔随机分为对照组、高脂组、高脂+低剂量(10mg·kg~(-1)·d~(-1))二氢杨梅素组和高脂+高剂量(40mg·kg~(-1)·d~(-1))二氢杨梅素组。高脂组给予高脂饲料,高脂+低二氢杨梅素组给予高脂饲料同时每天灌胃二氢杨梅素。24周后处死动物,检测血脂水平,取胸主动脉行苏丹Ⅳ染色检测斑块面积,颈总动脉石蜡切片,HE染色观察病理形态学变化,Western blot检测胸主动脉中自噬相关蛋白微管相关蛋白1轻链3(LC3)、Beclin-1和p62/SQSTM1的表达。结果:与对照组比较,高脂组的血清HDL、LDL、TC和TG水平均显著升高(均P0.05),胸主动脉管壁内表面呈弥漫性隆起,形成明显AS斑块,AS斑块区域占血管内膜总面积的百分比与对照组相比显著增加(P0.01),颈总动脉内膜增生,结构不完整,管腔形成明显AS斑块,斑块中大量泡沫细胞和脂质沉积,血管内中膜界限不清楚。高脂组兔主动脉弓中的Beclin-1、LC3-Ⅱ的表达和LC3-Ⅱ/LC3-Ⅰ的比值均显著降低(均P0.05),而p62的表达显著上调(P0.05)。与高脂组比较,高脂+高剂量二氢杨梅素组的血清HDL、LDL和TC水平均显著降低(均P0.05),胸主动脉管壁内表面隆起减少,AS斑块区域占血管内膜总面积的百分比显著降低(P0.01),总颈动脉AS病变程度明显减轻,主动脉弓中的Beclin-1、LC3-Ⅱ的表达和LC3-Ⅱ/LC3-Ⅰ的比值均显著增加(均P0.05),而p62的表达显著下调(P0.05)。高脂+低剂量二氢杨梅素组上述指标与高脂组比较差异均无统计学意义(均P0.05)。结论:二氢杨梅素能抑制高脂诱导新西兰兔AS的形成,其机制与促进细胞自噬有关。     

艾赛布考抑制兔动脉粥样硬化的作用及可能机制

目的:艾赛布考是普罗布考代谢稳定的衍生物,具有抗氧化、抗炎、抗增殖特性。本研究旨在探讨艾赛布考对高胆固醇血症兔腹主动脉损伤后动脉粥样硬化发展的影响。方法:45只雄性新西兰兔随机分为对照组、艾赛布考组、普罗布考组3组,每组15只,分别给予高脂饮食(对照组),高脂饮食+1%艾赛布考(艾赛布考组)或1%普罗布考(普罗布考组),2周后,行腹主动脉内膜球囊损伤术,继续药物干预10周。12周末,行血管内超声评价三组兔腹主动脉粥样硬化斑块面积和斑块负荷;通过免疫组织化学法观察斑块内巨噬细胞的含量,免疫组织化学法、实时定量聚合酶链式反应分别检测斑块组织内炎症因子细胞间黏附分子-1、单核细胞趋化蛋白-1、基质金属蛋白酶-9蛋白及信使核糖核酸的表达。结果:与对照组相比,艾赛布考组兔血中低密度脂蛋白胆固醇及氧化应激水平显著降低,腹主动脉粥样硬化斑块内巨噬细胞含量及炎症因子表达也降低,斑块面积及斑块负荷显著减少(P均0.01)。与普罗布考组相比,艾赛布考组兔腹主动脉斑块面积及斑块负荷降低更加显著,差异具有统计学意义(P均0.01)。结论:艾赛布考通过调脂、抗炎、抗氧化作用,抑制内膜损伤后动脉粥样硬化进展。     

急性脑梗死病人血清对氧磷酶1活性与颈动脉粥样硬化斑块的关系

目的探讨急性脑梗死病人血清对氧磷酶1(PON1)活性与颈动脉粥样硬化斑块的关系。方法选择295例急性脑梗死病人,通过超声测量动脉内膜中层厚度(IMT),结合斑块性质,将病人分为无斑块组(81例)、稳定斑块组(92例)、不稳定斑块组(122例)。通过测定血清PON1活性,结合病人的临床资料及生化指标,分析PON1活性与颈动脉粥样硬化斑块的关系。结果各组间PON1水平比较差异有统计学意义(P0.05),PON1水平从高到低依次为无斑块组(142.31±31.11)U/mL、稳定斑块组(118.34±27.99)U/mL、不稳定斑块组(98.17±28.11)U/mL。PON1活性与颈动脉IMT呈负相关(r=-0.411,P0.001)。多因素分析发现,PON1[OR=0.960,95%CI(0.948,0.972)]为动脉粥样硬化斑块发生的独立保护性因素。结论颈动脉粥样斑块的稳定性与PON1密切相关,PON1可能在颈动脉粥样硬化斑块形成过程中起到一定的抑制作用。     

黄芪注射液对冠心病患者胰岛素、血糖和血脂水平的影响

目的本实验通过高脂饮食建立早期高脂血症兔模型,观察普罗布考对胆固醇相关转运体以及炎症因子的影响。方法新西兰白兔36只,雄雌不拘,采用数字表法随机分为基础组(n=9)、基础+普罗布考组(每只77 mg/d,n=9)、高脂组(n=9)和高脂+普罗布考组(每只77 mg/d,n=9)。40天后观察普罗布考对血脂的影响;HE染色观察普罗布考对各组新西兰白兔腹主动脉斑块形成的影响;油红O染色观察普罗布考对各组新西兰白兔肝脏脂质蓄积的影响;定量PCR测定普罗布考对新西兰白兔腹主动脉、肝脏和小肠中胆固醇相关转运体基因表达的影响;Western blot以及免疫组化测定普罗布考对新西兰白兔腹主动脉、肝脏、小肠内胆固醇相关转运蛋白表达的影响;ELISA方法测定普罗布考对炎症因子的影响。结果与基础组相比,高脂组免血清总胆固醇(TC)、低密度脂蛋白胆固醇(LDL-C)、高密度脂蛋白胆固醇(HDL-C)、甘油三酯(TG)水平均明显升高;与高脂组比较,高脂+普罗布考组免血清TC、LDL-C、HDL-C、TG水平均明显下降;高脂组中有动脉斑块形成,肝脏脂质蓄积增多;高脂+普罗布考组中,普罗布考明显抑制斑块的形成,减少肝脏脂质蓄积;普罗布...     

JAZF1基因过表达对ApoE~(-/-)小鼠脂代谢及动脉粥样硬化的影响

目的探讨JAZF1基因过表达对ApoE-/-小鼠脂代谢及动脉粥样硬化(AS)的影响。方法将48只雄性ApoE-/-小鼠随机分为:高脂+空载(GF组)及高脂+JAZF1质粒组(JAZF1组)、高脂+生理盐水组(HF组)。检测各组血脂、生化指标、组织脂质含量、粪便胆汁酸及主动脉内膜粥样硬化病变。采用[1-14 C]醋酸盐腹腔注射,免疫荧光观察JAZF1基因过表达对ApoE-/-小鼠肝脏TC合成代谢及斑块巨噬细胞聚集的影响。结果JAZF1组肝脏JAZF1表达以及HDL-C/TC高于HF、GF组(P均0.05),而FBG、FIns、TC、胰岛素抵抗指数(HOMA-IR)、动脉粥样硬化指数(AI)、血脂综合指数(LCI)和肝脏TC含量低于HF、GF组(P均0.05);与HF组和GF组比较,JAZF1组血管内膜脂质堆积减少,主动脉内斑块泡沫细胞聚集较少,斑块面积、斑块面积/管腔面积、主动脉粥样斑块内巨噬细胞CD68表达、肝脏14 C标记TC放射活性及肝和小肠14 C标记TC放射活性降低(P0.05或P0.01)。结论 JAZF1基因过表达可减少ApoE-/-小鼠肝脏TC含量,并抑制TC合成,改善脂代谢,抑制巨噬细胞在斑块内的聚集,减轻和延缓AS的形成。     

普罗布考对高脂家兔胸主动脉内皮储备功能的保护作用

为观察口服普罗布考对高胆固醇血症和动脉粥样硬化免主动脉的内皮储备功能的影响,并探讨其可能作用机制。将26只新西兰白兔(体重1.5-2.5 kg)随机分为3组:正常饮食组(普通饮食,n=6)、高脂饮食组(高脂饮食,n=10)、普罗布考治疗组(高脂饮食+普罗布考200mg/kg,n=10)。在高脂饲养前和饲养后第12周,抽血测血清总胆固醇浓度。第12周后处死动物,取胸主动脉,检测离体胸主动脉环对乙酰胆碱与硝普钠的反应。结果发现,①普罗布考有降血脂作用(39.1％);②与正常饮食组相比,高脂血症兔胸主动脉对乙酰胆碱引起的最大的内皮依赖性舒张反应明显降低(0.65±0.14比0.16±0.04,P<0.05),普罗布考能明显保护高胆固醇血症所损伤的内皮依赖性舒张反应(两组最大血管舒张度分别为0.60±0.10比0.16±0.04,P<0.05);③3组对硝普钠所致的非内皮依赖性舒张反应均没有差别。结果提示普罗布考主要是通过降血脂和抗氧化两个途径来保护高脂家兔胸主动脉内皮储备功能。     

Probucol reduces plasma and aortic wall oxysterol levels in cholesterol fed rabbits independently of its plasma cholesterol lowering effect.

To understand further the antiatherogenic mechanism of probucol, the antioxidant effect of this agent was studied on specific cholesterol oxidation products in plasma and aortic wall in equally hypercholesterolemic New Zealand white rabbits. In order to maintain equal plasma total cholesterol levels, five control rabbits (C group) received a 1% followed by a 0.5% cholesterol enriched diet, while the probucol treated rabbits (C+P group) received a graded increase in the cholesterol supplemented diet from 1% to 3%; probucol supplementation was constant at 1%. After 9 weeks of feeding, the plasma oxysterols, cholest-5-ene-3 beta,7 alpha-diol, cholest-5-ene-3 beta,7 beta-diol, 5,6 beta-epoxy-5 alpha-cholestan-3 beta-ol, 5,6 alpha-epoxy-5 alpha-cholestan-3 alpha-ol and 5 alpha-cholestane-3 beta,5,6 beta-triol significantly increased over baseline levels in both experimental groups. However, the increase in all these products in plasma was 20-60% less in the C+P group than the C group (P < 0.05). Furthermore, the C+P aortic wall cholesterol oxide concentrations were 50-90% less than the C group (P < 0.05). The oxysterol pattern of the aortic wall was similar to plasma. Additionally, the aortic wall cholesterol content in the C+P group was 50% less than the C group (P < 0.05). The plasma cholesterol levels were not significantly different at any time point during the study and the cholesterol oxide content in the diets was the same. These results are consistent with the contention that the antioxidant properties of probucol serve as the basis for its antiatherogenic effects in vivo.     

Lack of effect of probucol on atheroma formation in cholesterol-fed rabbits kept at comparable plasma cholesterol levels

Rabbits were fed cholesterol for 14 weeks to study the effect of probucol on atheroma formation. Three groups of animals were investigated: group CHOL was fed 1% cholesterol and served as control for group P + CHOL. fed 1% cholesterol and 1% probucol from the onset till the end of the experiment: group CHOL + P received 1% cholesterol throughout the experiment and 1% probucol during the last 4 weeks only. Plasma cholesterol concentrations were monitored at frequent intervals and were modulated by dietary perturbations so that the areas under the curve expressing plasma cholesterol changes with time, were similar in probucol and non-treated rabbits. The efficacy of long-term probucol treatment was evidenced by a significant reduction in plasma apolipoprotein A-I throughout the experiment and lower plasma TBARs during the first 6 weeks, when the hypocholesterolemic effect of probucol was also seen. Two weeks prior to the termination of the experiment, the rabbits were injected with rabbit plasma labeled with [3H]cholesteryl linoleyl ether [( 3H]CLE). Aortic atheromatosis was quantified by determination of total and cholesteryl ester (CE). The aortic cholesterol content was related to the arch, thoracic and abdominal segments, to the surface area of each segment or its dry defatted weight. Total and esterified cholesterol were highest in the aortic arch in all 3 groups when related to any of the above mentioned parameters. No statistically significant difference in aortic total cholesterol and CE content was seen among the three groups studied. The [3H]CLE recovered in the aortic segment correlated with the CE content and the [3H]CLE (dpm)/mg CE in all segments was similar. No statistically significant difference in the [3H]CLE recovered in the aortic segments among the 3 groups was seen. We conclude that in cholesterol-fed rabbits, in which the plasma cholesterol levels were maintained at comparable levels, probucol treatment did not affect plasma CE influx into the aorta and did not attenuate development of aortic atherosclerosis.     

Decreased plasma membrane fluidity in the development of atherosclerosis in cholesterol-fed rabbits

Rabbits were fed a diet supplemented with 3% peanut oil or 3% peanut oil plus 0.5% cholesterol. Aortas from rabbits fed the cholesterol supplemented diet for 2 weeks were free of grossly visible lesions; however, aortas from rabbits fed this diet for 10 weeks exhibited extensive lesion development. Lesions were not observed in aortas of rabbits fed the high-fat supplemented diet. The fluorescence anisotropy of DPH was significantly (P = 0.0001) increased in plasma membranes isolated from aortas of rabbits fed the high-fat plus cholesterol vs. high-fat supplemented diet; the increase in fluorescence anisotropy observed after only 2 weeks on diet (0.201 +/- 0.002 vs. 0.144 +/- 0.002) was similar to that observed after 10 weeks on diet (0.244 +/- 0.002 vs. 0.193 +/- 0.001). The data support the hypothesis that plasma membrane fluidity [is decreased in atherosclerosis and indicate the decrease in membrane fluidity] occurs early in the development of the disease.     

普罗布考对高脂血症兔肝功能及胆汁酸受体表达的影响

目的观察普罗布考对高脂血症兔肝功能及肝脏胆汁酸受体(FXR)mRNA表达的影响。方法16只新西兰大白兔给予高脂饲料饲养8周后,随机分为:(1)高胆固醇组(n=8):继续饲以高脂饲料6周;(2)普罗布考组(n=8):在饲以高脂饲料的基础上给予1%普罗布考,共6周。正常饲料组(n=8):另选8只饲以普通饲料14周的兔为对照组。动态观察肝功能变化,实验结束后,采用半定量逆转录聚合酶链式反应(RT-PCR)法测定肝脏FXR mRNA的表达。结果①普罗布考治疗6周后,血清总胆固醇,低密度脂蛋白胆固醇(LDL-C)和高密度脂蛋白胆固醇(HDL-C)均明显下降;②普罗布考组谷丙转氨酶(ALT)(45.34±14.91)U/L及谷草转氨酶(AST)(49.68±15.84)U/L,较高胆固醇组[ALT(67.20±17.34)U/L,AST(81.36±22.97)U/L]均明显降低,P均<0.01;③与高胆固醇组比较,普罗布考组血清总胆汁酸(TBA)(46.11±18.58)mmol/L vs(56.34±20.67)mmol/L,总胆红素(T-BIL)均明显降低,为(3.04±1.06)mmol/L vs(5.34±1.38)mmol/L,P均<0.05;④肝脏FXR mRNA的表达明显增加,为0.86±0.05 vs 0.62±0.06,P=0.018。结论普罗布考具有护肝作用,其降低HDL-C可能与上调FXRmRNA的表达有关。     

普罗布考对动脉粥样硬化兔血红素氧合酶1表达的影响

目的观察血红素氧合酶1蛋白在兔主动脉粥样硬化病变和肝脏中的表达以及普罗布考对血红素氧合酶1表达的影响。方法16只新西兰大白兔建立动脉粥样硬化模型后,随机加喂普罗布考(n=8,普罗布考组)或淀粉(n=8,淀粉组)6周。观察两组兔以及正常新西兰大白兔(n=8,正常对照组)血脂、体重和血清丙二醛含量。采用免疫组织化学法测定主动脉和肝脏血红素氧合酶1蛋白的表达。结果与淀粉组相比,普罗布考组血红素氧合酶1在主动脉和肝脏内表达增多,动脉粥样斑块减少,血清总胆固醇、低密度脂蛋白胆固醇、高密度脂蛋白胆固醇和丙二醛明显降低。血红素氧合酶1在动脉内膜斑块、动脉平滑肌以及肝脏内的表达水平与血清丙二醛、主动脉斑块面积、内膜厚度、动脉内膜中膜厚度比均呈明显负相关(P均<0.05)。结论普罗布考在降低胆固醇的同时,还可能通过上调血红素氧合酶1发挥抗氧化作用,这可能是其抗动脉粥样硬化的重要途径。     

A diet high in saturated fat and sucrose alters glucoregulation and induces aortic fatty streaks in New Zealand White rabbits

A new and convenient animal model for studying peripheral vascular and coronary artery disease in diabetes was established in this study. Male New Zealand White rabbits weighing approximately 2 kg were divided into 2 groups: a normal control group fed standard laboratory chow and a diabetogenic diet-fed group received a high-fat/high-sucrose diet. The high-fat/high-sucrose diet (contained 10% lard and 37% sucrose) feeding was maintained for 6 months. Plasma total cholesterol, high-density lipoprotein (HDL) cholesterol, triglyceride, superoxide dismutase, nitric oxide, nitric oxide synthase, insulin, and glucose were quantitated at monthly or bimonthly intervals. The aortic fatty streak lesions were quantified following lipid staining with Sudan IV. The aortic samples were observed by electron microscopy. High plasma triglyceride and glucose concentrations were induced. At the end of 6 months, the aortic fatty streak lesions were present in the animals' vascular specimens. As far as we know, this is the first report that demonstrates that New Zealand White rabbits can develop obvious aortic fatty streaks by feeding a high-fat/high-sucrose diet. Our results suggest that New Zealand White rabbits fed a high-fat/high-sucrose diet would provide a convenient model for studying peripheral vascular-and coronary artery disease in diabetes.     

吡格列酮对高脂血症大鼠主动脉内皮细胞凋亡的作用

目的观察吡格列酮对高脂血症大鼠主动脉内皮细胞凋亡的影响,并探讨其可能的作用机制。方法清洁型SD大鼠26只,随机分为健康对照组(9只)、高脂饮食组(17只),高脂饮食组喂养12周后再随机分为模型组(8只)和吡格列酮组(9只),4周后,检测各组血脂水平,通过免疫组织化学法检测主动脉Bcl-2、Bax的表达,TUNEL染色法观察主动脉内皮细胞凋亡情况,计算细胞凋亡指数。结果 (1)高脂饮食组喂养12周后,血脂明显升高;给药4周后,与模型组比较,吡格列酮组TG、TC水平明显降低(P=0.000);(2)与健康对照组相比,模型组主动脉Bax蛋白表达明显增高(P=0.003),Bcl-2蛋白表达和Bcl-2/Bax比值明显降低(P=0.000);与模型组相比,吡格列酮组主动脉Bax蛋白表达明显降低(P=0.000),Bcl-2蛋白表达(P=0.001)和Bcl-2/Bax比值明显升高(P=0.000),且吡格列酮组主动脉内皮细胞凋亡指数较模型组明显降低,差异有统计学意义(17.5633±7.0584比6.0475±2.2370,P=0.000)。结论吡格列酮可改善高脂血症大鼠血脂水平,调节凋亡蛋白表达,减少主动脉内皮细胞凋亡。     

烟酸对高脂血症兔脂肪细胞胆固醇流出和肝X受体表达的影响

目的探讨烟酸对高脂血症兔脂肪细胞胆固醇流出和肝X受体（LXR）α、过氧化物酶体增殖物激活受体（PPAR）γmRNA表达的影响。方法选取12只健康雄性新西兰兔给予高胆固醇饲料培养8周,建立高胆固醇兔模型后,随机分为高胆固醇组（继续饲以高胆固醇饲料6周,n=6）,烟酸治疗组（在饲以高胆固醇饲料的基础上给予烟酸缓释剂0．2g·kg^-1·d^-1,共6周,n=6）,另选普通饮食14周雄性新西兰兔（n=6）作为对照组。实验结束后,取皮下脂肪行脂肪细胞培养,用液体闪烁计数器检测细胞内胆固醇流出,运用逆转录聚合酶链反应检测LXRα mRNA的表达。此外,在体外观察不同浓度的烟酸缓释剂（0．25、0．5、1、2mmol／L）对健康雄性新西兰兔脂肪细胞LXRα、PPARγ mRNA的影响。结果高胆固醇组脂肪细胞胆固醇流出率（5．94±1．26）％明显低于正常对照组（12．68±1．31）％,烟酸治疗组脂肪细胞胆固醇流出升高明显（16．39±3．32）％,3组间比较差异有统计学意义。逆转录聚合酶链反应显示烟酸治疗组较高胆固醇组LXRα mRNA表达高,与胆固醇流出率呈正相关。体外实验亦显示,烟酸缓释剂呈浓度依赖性升高脂肪细胞LXRα、PPARγ mRNA的表达。结论烟酸增加高脂血症兔脂肪细胞LXRα mRNA的表达及细胞内胆固醇流出。