耐力训练对ApoE~(-/-)小鼠AS形成及病理变化的干预作用研究

目的:采用复制的实验动物AS模型,观察耐力运动对AS形成的预防作用和对已经形成的AS的治疗或干预效果。方法:选取48只8周龄ApoE基因敲除(ApoE-/-)小鼠,饲以高脂高胆固醇膳食,实验动物分组为14周AS模型组(H组)、14周跑台运动组(HE组)、26周AS模型组(HH组)、14周造模+12周跑台运动组(H+E组),并选取8周龄C57BL/6J小鼠24只作为对照组,每组12只。令HE组和H+E组小鼠在活动跑台上进行耐力性运动(13 m/min,60 min/次,每周5次)。取主动脉组织制备主动脉根部冰冻切片,油红O染色评估AS斑块面积,HE染色分析主动脉组织病理学变化等。结果:(1)H组小鼠主动脉血管内膜可见大量AS斑块,其面积占血管腔总面积的41.79±6.93%,HE组主动脉斑块面积为25.07±7.04%,显著低于H组(P<0.01),且病变程度较H组明显减轻。(2)与H组相比,HH组小鼠主动脉AS病变进一步加重,斑块面积与血管腔总面积比例达58.80±6.40%,H+E组斑块面积为50.35±3.52%,显著低于HH组(P<0.05),且病变进展程度相对减缓。结论:14周耐力训练能有效地预防ApoE-/-小鼠AS的形成,12周耐力训练对ApoE-/-小鼠已经形成的AS起到了减缓其病变进展的作用。     

半枝莲总黄酮对ApoE基因敲除小鼠血清PLTP、IL-6、CRP表达的影响

 目的探讨半枝莲总黄酮对载脂蛋白E基因敲除小鼠AS病变形成早期血脂水平与血清磷脂转运蛋白（PLTP）、Il-6、C
反应蛋白（CRP）表达的影响。方法载脂蛋白E 基因敲除小鼠随机分为模型组、辛伐他汀组、银杏叶胶囊组、半枝莲总黄酮高、
中、低剂量组,取正常C57BL/6 小鼠为对照组,各6 只。除模型组、对照组给予等容量羧甲基纤维素钠外,其他各组分别给予阳性
对照药与受试药8 周。处死小鼠,ELISA 法检测血脂、PLTP、IL-6 及CRP 的表达水平。取主动脉制作切片、HE染色,观察形态学
变化。结果半枝莲总黄酮中、高剂量组TG、TC、LDL-C 水平明显低于模型组,高剂量组HDL-C 水平高于模型组,半枝莲总黄
酮各组PLTP、IL-6、CPR的表达水平较模型组明显降低,有统计学意义。PLTP与IL-6 水平呈正相关,与CRP 水平呈正相关,IL-6
与CRP 水平呈正相关。结论半枝莲总黄酮可通过降低载脂蛋白E 基因敲除小鼠TG、TC、LDL-C 水平,升高HDL-C 水平,降
低PLTP、IL-6、CPR 水平而发挥抗AS 的作用。     

Alterations in Carotid Parameters in ApoE–/– Mice Treated with a High-Fat Diet: A Micro-ultrasound Analysis

Information on the common carotid artery and cerebral microcirculation can be obtained by micro-ultrasound (µUS). The aim of the study described here was to investigate high-fat diet-induced alterations in vascular parameters in ApoE–/– mice. Twenty-two ApoE–/– male mice were examined by µUS and divided into the standard diet (ApoE–/–_SD) and high-fat diet (ApoE–/–_HF) groups. The µUS examination was repeated after 4 mo (T₁). Carotid stiffness, reflection magnitude and reflection index were measured; the amplitudes of the first (W₁) and second (W₂) local maxima, the local minimum (W_b) and the reflection index (RI_WIA?=?W_b/W₁) were assessed with wave intensity analysis. At T₁, ApoE–/–_HF mice had increased carotid stiffness (1.48 [0.36] vs. 1.88 [0.51]) and reflection magnitude (0.89 [0.07] vs. 0.94 [0.07]) values. Longitudinal comparisons highlighted increases in carotid stiffness for ApoE–/–_HF mice (from 1.37 [0.25] to 1.88 [0.51] m/s) but not for ApoE–/–_SD mice (from 1.40 [0.62] to 1.48 [0.36] m/s). ApoE–/–_HF mice exhibited carotid artery stiffening and increased wave reflections.     

ApoE与骨质疏松症相关性的研究进展

骨质疏松症（osteoporosis,OP）作为一种比较常见的骨代谢疾病,与高血脂症间存在着一定的关联,临床上同时患有这两种疾病的现象比较常见。当骨吸收增加而骨形成减少时,骨代谢失衡,就会发生OP。载脂蛋白E（ApoE）是血浆中主要的载脂蛋白之一,ApoE功能异常是引起高血脂症的关键。近年来依托ApoE基因敲除鼠模型,在ApoE调节血脂机制及高脂血症与OP的发生过程相关性的研究有了诸多新发现,拓宽了固有认知。本文主要汇总了ApoE近5年与骨相关的研究,分析其影响OP的发生过程的机制,从宏观的血脂和细胞层面到微观的氧化应激和炎症层面,总结了ApoE对骨代谢的重要调节作用,以期为后续研究、新药物筛选及临床应用提供参考依据。     

Exclusion of the apoE gene in autosomal dominant retinitis pigmentosa

Our purpose was to search for mutations in the apolipoprotein E (apoE) gene and to evaluate the role of apoE polymorphisms in the occurrence of autosomal dominant retinitis pigmentosa (ADRP). The ApoE gene coding sequence was analyzed in 51 unrelated patients affected with ADRP. A screening for mutations by SSCP and an analysis of the apoE polymorphisms were performed using PCR and restriction enzymatic digestion. No abnormal patterns of migration were observed by SSCP analysis. No significant statistical difference was seen between our ADRP population and the French general population for apoE allele frequency. From these results we report that the apoE gene does not seems to be involved in our ADRP population.     

The apolipoprotein E ɛ4 allele and memory performance in HIV-1 seropositive subjects: differences at baseline but not after acute oral lorazepam challenge

Rationale  The APOE ɛ4 allele, an established genetic risk factor for late-onset Alzheimer’s disease, has been linked to an increased risk for dementia especially in older individuals with HIV-1 infection. This allele has also been associated with increased memory impairment following oral lorazepam challenge in healthy elderly. Lorazepam and other benzodiazepines are widely prescribed in individuals with HIV-1 infection who are at increased risk for cognitive impairment. Objective  The aim of this study was to examine if the ɛ4 allele influences lorazepam-induced memory deficits in this population. Materials and methods  Forty-one non-demented, HIV-1 seropositive adults (15 ɛ4 carriers, mean age = 43.47 ± 8.25; 26 ɛ4 non-carriers, mean age = 46.77 ± 8.56) participated in a double-blind, placebo-controlled crossover design, receiving single acute oral doses of lorazepam 0.5, 1.0 mg, or placebo over three sessions, each 1 week apart. Standardized neuropsychological assessments, including measures of immediate and delayed verbal recall, were conducted at baseline and at 1, 2.5, and 5 h post-drug administration in each condition. Results  Acute lorazepam administration produced dose- and time-dependent impairments in measures of verbal recall. However, the e4 allele did not modulate these adverse effects. An APOE ɛ4 group by time interaction was also found such that the APOE-ɛ4-positive subjects had significantly better immediate and delayed verbal recall than the negative subjects at baseline assessment, but the groups did not significantly differ at any subsequent time point. Conclusion  Future studies should clarify the role of ɛ4 in the modulation of drug-induced cognitive toxicity and baseline performance and their relationship to progressive decline, especially in older individuals with HIV-1 infection, a group at increased risk for dementia. All analyses were repeated (not reported here, available upon request) in the subgroup of individuals currently meeting CDC surveillance case definition for AIDS (Center for Disease Control and Prevention 1992; n = 30; 12 ɛ4+/18 ɛ4−). The pattern of findings was replicated.     

PACAP deficiency aggravates atherosclerosis in ApoE deficient mice

Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) plays an important role in cytoprotection, inflammation and cardiovascular regulation. Thus, we studied the involvement of PACAP in atherogenesis. Differentiated human THP-1 macrophages (MΦ) were stimulated with oxidized low-density lipoproteins (oxLDL) and the influence of PACAP38 treatment on lipid content and TNF release was determined. To test the effect of PACAP deficiency (PACAP^?/?) on the development of atherosclerosis under standard chow (SC) or cholesterol-enriched diet (CED) in vivo, PACAP^?/? mice were crossbred with ApoE^?/? to generate PACAP^?/?/ApoE^?/? mice. Blood cholesterol and triglyceride levels were quantified. Lumen stenosis in the brachiocephalic trunk, cellularity and amounts of pro-inflammatory as well as autophagy-, apoptosis- and necroptosis-relevant proteins were analysed in atherosclerotic plaques by quantitative immunohistochemistry. In vitro, PACAP38 inhibited oxLDL-induced intracellular lipid storage as well as TNF release in MФ. In vivo, after SC, but not under CED, PACAP^?/?/ApoE^?/? mice showed an increased lumen stenosis compared to ApoE^?/? mice. In atherosclerotic plaques of PACAP^?/?/ApoE^?/? mice, the immunoreactive areas of TNF⁺, IL-1β⁺, autophagic, apoptotic and necroptotic cells were increased. In contrast, the overall cell density was decreased compared to ApoE^?/? under SC, while no differences were seen under CED. Similar plasma cholesterol levels were observed in PACAP^?/?/ApoE^?/? and ApoE^?/? mice under the respective feeding regime. Thus, PACAP^?/-/ApoE^?/? mice represent a novel mouse model of accelerated atherosclerosis where CED is not required. Our data indicate that PACAP acts as an endogenous atheroprotective neuropeptide. Thus, stable PACAP agonists may have potential as anti-atherosclerotic therapeutics. The specific PACAP receptor(s) mediating atheroprotection remain(s) to be identified.     

Cerebral hemorrhage and apoE

The ɛ4 allele of apolipoprotein E (apoE) is found more commonly among patients with Alzheimer’s disease (AD) than in the normal population. ApoE is associated with brain amyloid, a component of cerebral amyloid angiopathy (CAA), which is both a pathological feature of AD and a frequent cause of lobar intracerebral hemorrhage (ICH). We hypothesized that the frequency of ɛ4 allele is higher in patients with CAA-related ICH than in hypertensive ICH and in the normal population. To test this hypothesis we compared the frequency of apoE alleles in four populations: 24 patients with lobar ICH, 24 matched patients with hypertensive ICH, 24 matched normal controls, and 173 population controls. Although there was a tendency to a higher frequency of apoE ɛ4 in lobar ICH patients, we found no significant differences in the frequency of this allele between the four studied populations. In addition we did not confirm the finding of some authors of a higher frequency of apoE ɛ2 in patients with lobar ICH than in the normal population. Previous studies on the subject are discussed. The relationship between apoE polymorphism and lobar CAA-related ICH remains to be clearly defined. Received: 28 August 1998 Received in revised form: 19 February 1999 Accepted: 23 February 1999