Beneficial effect of an omega-6 PUFA-rich diet in non-steroidal anti-inflammatory drug-induced mucosal damage in the murine small intestine

AIM: To investigate the effect of a fat rich diet onnon-steroidal anti-inflammatory drug(NSAID)-induced mucosal damage in the murine small intestine.METHODS: C57BL6 mice were fed 4 types of diets with or without indomethacin.One group was fed standard laboratory chow.The other groups were fed a fat diet consisting of 8% w/w fat,beef tallow(rich in SFA),fish oil,(rich in omega-3 PUFA),or safflower oil(rich in omega-6 PUFA).Indomethacin(3 mg/kg) was injected intraperitoneally from day 8 to day 10.On day 11,intestines and adhesions to submucosal microvessels were examined.RESULTS: In the indomethacin-treated groups,mucosal damage was exacerbated by diets containing beef tallow and fish oil,and was accompanied by leukocyte infiltration(P < 0.05).The mucosal damage induced by indomethacin was significantly lower in mice fed the safflower oil diet than in mice fed the beef tallow or fish oil diet(P < 0.05).Indomethacin increased monocyte and platelet migration to the intestinal mucosa,whereas safflower oil significantly decreased monocyte and platelet recruitment(P < 0.05).CONCLUSION: A diet rich in SFA and omega-3 PUFA exacerbated NSAID-induced small intestinal damage via increased leukocyte infiltration.Importantly,a diet rich in omega-6-PUFA did not aggravate inflammation as monocyte migration was blocked.     

Roles of kupffer cell polarization and hepatic stellate cell activation in hepatic inflammation and fibrosis in NAFLD

正Objective To investigate the roles of Kupffer cell polarization and HSC activation in the development of hepatic inflammation and fibrosis in progression of non-alcoholic fatty liver disease(NAFLD).Methods C57BL/6 mice were fed with high fat(HF)diet and methioninecholine-deficient(MCD)diet to induce experimental non-alcoholic fatty liver(NAFL)and non-alcoholic     

Hyperhomocysteinemia independently causes and promotes atherosclerosis in LDL receptor-deficient mice

Background Hyperhomocysteine is an independent risk factor of coronary heart disease （CHD）. However, whether hyperhomocys teine affects the progression of atherosclerosis is unclear. In the present study, we examined the effect of hyperhomocysteine on the forma tion of atherosclerosis in low-density lipoprotein receptor-deficient （LDLr ） mice. Methods Forty-eight 7-week-old LDLr/ mice were assigned to the following groups： mice fed a standard rodent diet （control group）, mice fed a high-methionine diet （high-methionine group）, mice fed a high-fat diet （high-fat group）, and mice fed a diet high in both methionine and fat （high-methionine and high-fat group）. At the age of 19, 23, and 27 weeks, four mice at each interval in every group were sacrificed. Results At the end of the study, mice did not show atherosclerotic lesions in the aortic sinus and aortic surface until 27 weeks old in the control group. However, atherosclerotic lesions developed in the other three groups at 19 weeks. The amount of atherosclerotic lesions on the aortic surface was lower in the high-methionine group than in the high-fat group （P 〈 0.001）. Atherosclerotic lesions on the aortic surface in the high-methionine and high-fat group were the most severe. The mean area of atherosclerotic lesions in the aortic sinus compared with atherosclerotic lesions on the aortic surface was lower in the high-methionine group than in the high-fat group （P 〈 0.001）. Atherosclerotic lesions in the aortic sinus in the high-methionine and high-fat group were the most severe. Conclusions Homocysteinemia accelerates atherosclerotic lesions and induces early atherosclerosis independently in LDLrmice. Reducing the level of homocysteinemia may be beneficial for prevention and treatment of CHD.     

Combination curcumin and vitamin E treatment attenuates diet-induced steatosis in Hfe~(-/-)mice

AIM To investigate the synergistic hepato-protective properties of curcumin and vitamin E in an Hfe~(-/-)high calorie diet model of steatohepatitis.METHODS Hfe~(-/-)C57BL/6J mice were fed either a high calorie diet or a high calorie diet with 1 mg/g curcumin; 1.5 mg/g vitamin E; or combination of 1 mg/g curcumin + 1.5 mg/g vitamin E for 20 wk. Serum and liver tissue were collected at the completion of the experiment. Liver histology was graded by a pathologist for steatosis, inflammation and fibrosis. RNA and protein was extracted from liver tissue to examine gene and protein expression associated with fatty acid oxidation, mitochondrial biogenesis and oxidative stress pathways.RESULTS Hfe~(-/-)mice fed the high calorie diet developed steatohepatitis and pericentral fibrosis. Combination treatment with curcumin and vitamin E resulted in a greater reduction of percent steatosis than either vitamin E or curcumin therapy alone. Serum alanine aminotransferase and non-alcoholic fatty liver disease(NAFLD) activity score were decreased following combination therapy with curcumin and vitamin E compared with high calorie diet alone. No changes were observed in inflammatory or fibrosis markers following treatment. Epididymal fat pad weights were significantly reduced following combination therapy, however total body weight and liver weight were unchanged. Combination therapy increased the m RNA expression of Adipo R2, Ppar-α, Cpt1 a, Nrf-1 and Tfb2 m suggesting enhanced fatty acid oxidation and mitochondrial biogenesis. In addition, combination treatment resulted in increased catalase activity in Hfe~(-/-)mice. CONCLUSION Combination curcumin and vitamin E treatment decreases liver injury in this steatohepatitis model, indicating that combination therapy may be of value in NAFLD.     

Effects of selenium supplement on atherogenesis of Apo E-knockout mice fed high fat diet

<正>Objective To investigate the effects of selenium supplement on atherogenesis and endothelial function in Apo E-knockout mice fed high fat diet.Methods Apo Eknockout nice fed with selenium-deficient and high fat diet were randomly allocated into 3 groups based on ran-     

Adiponectin Attenuates Hypoxia/Reoxygenation-Induced Cardiomyocyte Injury Through Inhibition of Endoplasmic Reticulum Stress

Objective TanshinoneⅡ-A(Tan),a bioactive diterpene isolated fromSalvia miltiorrhiza Bunge(Danshen),possesses anti-oxidant and anti-in-flammatory activities.The present study investigated whether Tan can reduce and stabilize atherosclerotic plaques in Apolipoprotein E knockout(ApoE-/-) mice maintained on a high cholesterol diet(HCD).Methods and Results Six week-old mice challenged with HCD were ran-domly assigned to 4 groups: C57BL/6J,ApoE-/-,ApoE-/-+30 mg/kg.d Tan and ApoE-/-+10 mg/kg.d Tan.After 16 weeks o...     

Effects of resistant dextrin on liver fat deposition and the AMPK signaling pathway in high-fat diet-fed mice

正Objective To study the effects of resistant dextrin(RD) on liver fat deposition in high-fat diet-fed (HFD)mice,and to further explore whether it can regulate the AMPK signaling pathway or not.Methods Thirty-six 4-week-old male C57BL/6 mice were randomly divided into three groups:normal control group (chow),high-fat diet group (HFD),and high-fat diet+resistant dextrin group (HFD+RD,10 g·kg~(-1)·d~(-1)).After 12 weeks     

Hydrogen-rich Saline Reduces Atherogenesis in Apolipoprotein E Knockout Mice Fed a High-fat Diet by Inhibiting the Non-HDL-mediated Arterial Inflammation and Promoting the Expression of Genes Involving Reverse Cholesterol Transport

Aim Hydrogen(dihydrogen,H2) is an effective antioxidant to reduce oxidative stress and oxidative stress is implicated in atherogene-sis.In this study we examined whether hydrogen-saturated saline can prevent atherosclerosis in apolipoprotein E knockout(apoE-/-) mice fed either chowdiet or high-fat diet,and characterized the underlying molecular mechanisms.Methods and Results The atherosclerotic lesion formation displayed by oil red O staining positive area was reduced significantly in either aortic root section or aortic arch en face in hydrogen administrated apoE-/-mice fed either chowdiet or high-fat diet,compared to the control.Plasma analysis by enzymatic method showed that total cholesterol(TC) and non-high-density lipoprotein cholesterol(non-HDL-C)were remarkably decreased by treatment with hydrogen.Western blot analysis revealed a significant decrease of both plasma apoli-poprotein B(apoB) level and hepatic expression of apoB after hydrogen treatment,suggesting hydrogen could downregulate the expression of the major protein constituent of non-HDL.In addition,spectrophotometric measurement showed that plasma levels of malondi-aldehyde(MDA) and serum amyloid Awas decreased and paraoxonase-1 activity was increased in mice treated with hydrogen,suggesting plasma lipid oxidation and peroxidation was impaired by hydrogen treatment.Besides,the MDA content of the non-HDL,whichseparated by ultracentrifugation from the plasma of mice treated with and without hydrogen,was reduced by hydrogen,suggesting the oxidation of non-HDL was impaired by hydrogen.Moreover,we found hydrogen treatment significantly suppressed the production of tumor necrosis factor-α(TNF-α) and interleukin-6 in RAW264.7 macrophages after stimulation with the isolated non-HDL,suggesting hydrogen reduces atherogenesis by inhibiting non-high-density lipoprotein(HDL)-mediated inflammation.Furthermore,immunohis-tochemistry of aortic valve sections revealed that hydrogen attenuated lesion formation by suppressing the expression of several proin-flammatory factors and decreasing vessel wall infiltration of macrophages,indicating hydrogen-treatment reduces arterial inflammation.Besides,real-time PCR and western blot analysis disclosed that the expression of several transporter genes involved in the process ofreverse cholesterol transport,including hepatic scavenger receptor class B type I(SR-BI),ATP-binding cassette(ABC) transporters ABCG8,ABCB4,ABCB11,and macrophage SR-BI,were all induced by hydrogen treatment.Conclusion These results re-vealed that administration of hydrogen-rich saline reduces atherogenesis in apoE-/-mice fed a high-fat diet by inhibiting the non-HDL-mediated arterial inflammation and promoting the expression of genes involving reverse cholesterol transport.     

Effect of adenosine A2A receptor agonist combined with bone marrow mesenchymal stem cells transplantation on the negative immune regulation in mice with acute liver failure

正Objective To investigate the therapeutic effect and possible mechanism of adenosine A2A receptor agonist(CGS21680)combined with bone marrow mesenchymal stem cells(BMMSC)transplantation in acute liver failure(ALF).Methods Fifty male C57BL/6 mice,6-8 weeks old,were fed with standard diet for 1 week and randomly divided into 5 groups according to random number table:     

小鼠腹主动脉斑块模型建立的两种方法及超高场强磁共振成像的应用价值

目的 探讨建立腹主动脉粥样硬化斑块模型的方法及超高场强磁共振成像(MRI)在活体监测及量化小鼠腹主动脉粥样硬化斑块中的应用价值.方法 高脂饮食法小鼠腹主动脉粥样硬化斑块模型的建立及磁共振检测(高脂饮食组):选择3批10～12月龄apoE-/-小鼠13只、WT鼠3只高脂饮食喂养,分别于喂养前、喂养3个月、喂养6个月3个时期进行小鼠腹主动脉7.0 T磁共振活体扫描.血管紧张素Ⅱ(AngⅡ)灌注法小鼠腹主动脉粥样硬化斑块模型的建立及磁共振检测(AngⅡ灌注组):选用10只6月龄apoE-/-小鼠,分为AngⅡ1000 ng·kg-1·min-1组3只、AngⅡ500 ng·kg-1·min-1组3只(以上两组均在背部埋置AngⅡ缓释泵14 d)和对照组为4只(埋置生理盐水缓释泵),分别于灌注前后行磁共振扫描,选用FLASH T1WI黑血及MSME-T2WI-PDWI双回波序列.高脂饮食组依次在各时期扫描后分别处死3、5、5只小鼠,AngⅡ灌注组于装泵后14 d行磁共振扫描,然后处死本组小鼠,取处死小鼠的肾动脉段腹主动脉制作病理切片,进行苏木素-伊红(HE)染色、Masson胶原纤维(CME)染色.每只小鼠选5～7层肾动脉段腹主动脉病理图像及多对比MRI图像,分别测量外腔面积(VOA)、内腔面积(LA),计算管肇面积(VWA)并进行MRI与病理测量结果的相关性分析.结果 两种方法建立的小鼠模型,其腹主动脉MRI与病理切片均可见不稳定斑块形成.高脂饮食组随着高脂饮食时间的延长,斑块进展,VWA不断增加,3个时期VWA方差分析F=29.94(P<0.05),斑块信号于PDWI、T2WI逐渐增加,且不均匀.高脂饮食组MRI测量的斑块面积与病理测量的斑块面积有较高的-致性(高脂喂养前、喂养3和6个月3个时期r值分别为0.84、0.95、0.90).病理切片中斑块成分与磁共振显示信号一致,均表现为脂质成分增加,纤维成分减少.AngⅡ1000 ng·kg-1·min-1组AngⅡ灌注后斑块面积与灌注前比较差异有统计学意义(P=0.017),分别为(2.65±0.48)mm2和(1.21±0.21)mm2,部分小鼠可见夹层动脉瘤形成.AngⅡ500 ng·kg-1·min-1组灌注后斑块面积也比灌注前有所进展,面积分别为(1.01±0.17)mm2和(0.85±0.11)mm2,MRI测量的斑块面积与病理测量的斑块面积有较高的一致性(r值为0.93).结论 AngⅡ灌注显著加快动脉粥样硬化进展并促进腹主动脉夹层动脉瘤形成,长期高脂饮食亦可形成晚期斑块.超高场强MRI多种序列黑血技术的综合应用能显示小鼠腹主动脉粥样硬化斑块的进展,其检测分析斑块大小结果与病理表现基本一致,对斑块成分的判定亦有一定价值.     

The TNF alpha converting enzyme (TACE/ADAM17) is expressed in the atherosclerotic lesions of apolipoprotein E-deficient mice: possible contribution to elevated plasma levels of soluble TNF alpha receptors

TNF alpha converting enzyme (TACE) critically regulates the inflammatory processes as it releases from the cell surface several transmembrane proteins, including TNFalpha (TNF) and its receptors TNFR1 and TNFR2. We investigated the expression of TACE in atherosclerotic lesions of apolipoproteinE-deficient (apoE (-/-)) mice. Five-week-old apoE(-/-) male mice were fed a high-fat diet and examined at 5, 10, 15 and 25 weeks of age. A group of wild-type C57BL/6 mice (WT) fed the high-fat diet for 25 weeks was included. In apoE(-/-) mice, lesions progressed with time in both aortic sinus and arch, in which TACE immunostaining also increased particularly between 5 and 15 weeks. TACE expression was also observed in human atherosclerotic plaques. The plasma levels of soluble TNFR1 and TNFR2 rose with atherosclerosis. In the 25-week-old WT mice, no lesions were observed and the plasma levels of TNFRs were 17% of those of age-matched apoE(-/-) mice. Incubated aortas of 25-week-old apoE(-/-) mice released much higher amounts of sTNF and sTNFRs than did aortas of 5-week-old apoE(-/-) mice or 25-week-old WT mice. Active TACE was expressed at the surface of macrophages isolated from apoE(-/-) mice. In conclusion, TACE expression is associated with lesions in atherosclerosis-prone sites. Our data suggest that atherosclerotic lesions-expressing TACE may contribute to the elevated levels of circulating sTNFRs.     

动脉粥样硬化斑块内FIZZ1表达促进平滑肌细胞清道夫受体-A上调

目的探讨ApoE基因敲除鼠动脉粥样硬化斑块内FIZZ1表达情况及其对平滑肌细胞清道夫受体A(SR-A)表达的影响.方法C57BL/6J ApoE基因敲除鼠及C57BL/6J野生型小鼠各9只,分别喂养高脂饲料及普通饲料,24周后处死小鼠,石蜡包埋血管后做连续切片,行HE染色及FIZZ1免疫组化.用氧化型低密度脂蛋白(ox-LDL)以及终浓度分别为3×10-6mmol/L、9×10-6mmol/L、2.7×10-5mmol/L的FIZZ1刺激培养的平滑肌细胞,激光共聚焦显微镜确认SR-A表达后,流式细胞术检测FIZZ1对ox-LDL诱导的平滑肌细胞SR-A表达的影响.结果ApoE基因敲除鼠高脂饲养24周后,主动脉根部明显形成动脉粥样硬化,可见FIZZ1在动脉粥样硬化斑块内明显表达,同龄野生型C57BL/6J鼠正常血管壁内,未见FIZZ1表达,重组FIZZ1能明显促进ox-LDL诱导的平滑肌细胞SR-A表达(与对照组比较,P<0.01).结论C57BL/6J野生型小鼠正常血管不表达FIZZ1,C57BL/6JApoE基因敲除鼠动脉粥样斑块表达FIZZ1,FIZZ1促进ox-LDL诱导的平滑肌细胞SR-A表达,提示FIZZ1可能在ApoE基因敲除鼠动脉粥样硬化进展中起一定的促进作用.     

Low carbohydrate, high protein diet promotes atherosclerosis in apolipoprotein E/low-density lipoprotein receptor double knockout mice (apoE/LDLR(-/-))

Although in apoE/LDLR(-/-) mice atherosclerotic plaques develop spontaneously, various atherogenic diets (e.g. Western diet) are frequently used to accelerate the disease in this model. The objective of this study was to compare the effects on atherosclerosis of Western diet and other types of high-fat, high cholesterol, hypertriglyceridemic diets with the effects of the low carbohydrate, high protein (LCHP) diet. 16-18 week old mice with pre-established atherosclerosis were assigned to experimental groups and fed for the next 10 weeks with control diet, margarine diet (margarine 7%), hypertrigliceridemic diet (fructose 62%), high-fat diet (Western diet), high cholesterol diet (egg yolk diet) or with LCHP diet. No differences in body weight were observed among experimental groups. Plasma cholesterol concentration was significantly increased in egg yolk diet- and LCHP diet-fed apoE/LDLR(-/-) mice as compared to other types of diets. Plasma concentration of triacylglycerols was significantly elevated in egg yolk diet- and LCHP diet-fed apoE/LDLR(-/-) mice. The area of atherosclerotic plaques in the aortic root was substantially increased in LCHP diet-fed mice as compared to other types of diets. Furthermore, in brachiocephalic arteries of LCHP diet-fed mice there was evidence of plaque rupture. In conclusion, the LCHP diet promoted atherosclerosis in apoE/LDLR(-/-) mice more intensively than classical Western diet and favored the development of unstable lesions.     

Effect of Chlamydia pneumoniae infection and hyperlipidaemia on the expression of PPARgamma, P50 and c-Fos in aortic endothelial cells in C57bL/6J mice

OBJECTIVE: To investigate the effect of C. pneumoniae infection and/or hyperlipidaemia on the expression of peroxisome proliferator-activated receptor gamma (PPARgamma), nuclear factor-kappa B (NF-kappaB) and activated protein-1 (AP-1) in aortic endothelial cells in C57BL/6J mice. METHODS AND RESULTS: Forty-eight, 8-week-old female C57BL/6J mice were divided into four groups:A, B, C and D (each twelve mice). Group A (as blank control) and B were fed a regular diet. Group C and D were fed an atherogenic diet (consisting of 15% fat, 2.5% cholesterol and 0.5% sodium cholate). Group B and D were infected with C. pneumoniae. Fourteen weeks later, the expression of PPARgamma, P50 (subunit of NF-kappaB) and c-Fos (subunit of AP-1) was determined by indirect immunofluorescence in the aortic endothelial cells. Slides of aortic sinus were prepared by cryosection, and stained with Sudan IV for examination of atherosclerotic plaque.The score of atherosclerotic plaque was determined by microscopy. The score of atherosclerotic plaque in group B was not increased, while it was significantly higher in groups C and D (P < 0.01), still the score in group D was higher than in group C (P < 0.01).The expression of PPARgamma, NF-kappaB and AP-1 in endothelial cells in aortic sinus was upregulated in group B, C and D, in comparison with group A (P < 0.05). There was no significant difference among groups B, C and D. CONCLUSION: The expression of PPARgamma, NF-kappaB and AP-1 was upregulated in the endothelial cells in mice infected with C. pneumoniae and/or fed with an atherogenic diet. An atherogenic diet or this diet combined with C. pneumoniae infection accelerated the process of atherosclerosis. The diet infected with C. pneumoniae alone would not accelerate this process. PPARgamma might play an anti-atherosclerotic role in this process.     

In vivo uptake of radiolabeled MDA2, an oxidation-specific monoclonal antibody, provides an accurate measure of atherosclerotic lesions rich in oxidized LDL and is highly sensitive to their regression

To determine whether labeled antibodies against oxidized LDL (OxLDL) offer advantages for quantifying atherosclerosis, we compared in vivo aortic uptake of (125)I-labeled MDA2, a monoclonal antibody against malondialdehyde-lysine epitopes), atherosclerotic surface area, and aortic weight in Watanabe heritable hyperlipidemic and New Zealand White rabbits and in low density lipoprotein receptor-deficient (LDLR(-/-)) and apolipoprotein E-deficient (apoE(-/-)) mice. Absolute and specific uptakes of (125)I-MDA2 were significantly greater in plaque than in normal aortas. Uptake of (125)I-MDA2 significantly correlated with aortic weight and percent atherosclerotic surface area in rabbits and mice. To assess whether (125)I-MDA2 uptake reflects changes in lesion content of OxLDL, in a separate study, extensive atherosclerosis was induced in 4 groups of LDLR(-/-) mice by feeding them a high fat/cholesterol diet for 6 months. A baseline group was euthanized at this time. The remaining groups were fed "regression" diets (chow or chow+1% vitamin E+0.05% vitamin C) or the high fat/cholesterol diet for 6 more months. When atherosclerosis was measured as percent surface area or aortic weight, there was strong progression in the high fat/cholesterol group, moderate progression in the chow group, and no progression in the chow+vitamin E+vitamin C group compared with the baseline group. The (125)I-MDA2 method also yielded a significant increase in atherosclerosis in the high fat/cholesterol group but significant decreases in the chow and chow+vitamin E+vitamin C groups. Immunocytochemistry showed fewer oxidation-specific epitopes in lesions from the chow and chow+vitamin E+vitamin C groups. Thus, the uptake of (125)I-MDA2 correlates well with traditional measures of atherosclerosis but also reflects reduced plaque OxLDL content after hypocholesterolemic intervention.     

瑞舒伐他汀对载脂蛋白E基因敲除小鼠血管内皮黏附性和氧化应激的抑制作用

目的 观察瑞舒伐他汀对血管内皮黏附性及氧化应激的抑制作用.方法 载脂蛋白E(apoE)基因敲除鼠80只,C57BL/6小鼠20只,均为8～9周龄.将apoE基因敲除鼠分为2、6周模型对照组各10只和药物治疗组各30只,C57BL/6小鼠分为2、6周正常对照组各10只.治疗组每日1次皮下注射不同浓度的瑞舒伐他汀,剂量分别为1、5 mg/kg和20 mg/kg;药物处理满2周或6周时,心内穿刺取血,并收获小鼠主动脉.结果 治疗组经瑞舒伐他汀5 mg/kg和20 mg/kg治疗后,血浆总胆固醇明显下降,2周时为(480.7±35.3)mmol/L和(371.5±27.1)mmol/L,6周时为(400.1±37.6)mmol/L和(305.0±19.3)mmol/L,与相应模型对照组[2周(675.0±42.0)mmol/L和6周(660.0±44.3)mmol/L]比较,差异有统计学意义(P＜0.05或P＜0.01);但三酰甘油和高密度脂蛋白胆固醇均无明显变化.治疗组经瑞舒伐他汀20 mg/kg治疗2周后,主动脉内皮单核细胞黏附率较模型对照组明显下降,分别为(2.24±0.72)%和(3.76±2.53)%(P＜0.05);6周后下降更为明显,分别为(1.94±0.40)%和(3.95±2.61)%(P＜0.01).瑞舒伐他汀还可抑制小鼠主动脉细胞色素b245(P22phox)表达和活性氧物质产生,两者表达模型对照组分别为(3.22±1.53)%和(4.75±2.62)μg/L,瑞舒伐他汀20 mg/kg治疗6周后,分别为(1.41±0.72)%和(2.72±0.88)μg/L,差异均有统计学意义(P＜0.05).结论 瑞舒伐他汀具有抑制血管内皮黏附性及抗氧化应激的作用.     

C3H apoE(-/-) mice have less atherosclerosis than C57BL apoE(-/-) mice despite having a more atherogenic serum lipid profile

Wild-type C57BL mice are known to be susceptible to diet-induced atherosclerosis, whilst C3H mice are resistant. We investigated the effect of these background strains on the hyperlipidaemia and atherosclerosis that develops in mice deficient in apolipoprotein E (apoE(-/-)). Male and female apoE(-/-) mice on C3H/HeNHsd (C3H) and C57BL/6J (C57) backgrounds were fed atherogenic Western diet for 12 weeks. Serum cholesterol and triglyceride concentrations were measured and atherosclerosis quantified in the aortic sinus. C3H apoE(-/-) mice fed normal diet had 1.5 2 fold higher serum cholesterol levels than C57 apoE(-/-) mice and 4-5 fold higher serum triglyceride concentrations. Feeding Western diet caused a 4-5 fold increase in serum cholesterol in all mice, but levels of triglyceride were either attenuated or were unaffected in C3H apoE(-/-) and C57 apoE(-/-) mice, respectively. C3H apoE(-/-) mice had approximately 2 fold higher serum cholesterol and 4 fold higher triglyceride concentrations than the C57 apoE(-/-) mice throughout the study. Serum triglyceride concentrations were 35-108% higher in male C3H apoE(-/-) than female C3H apoE(-/-) mice. Most of the lipids were present in the very low density lipoprotein (VLDL)/chylomicron fraction in both strains of mice whether they were fed normal or Western diet. Notwithstanding the lower plasma lipid concentrations, atherosclerotic lesion areas were more than 2-fold larger in C57 apoE(-/-) than in C3H apoE(-/-) mice (males 68 +/- 11 x 10(3) vs 30 +/- 6 x 10(3) females 102 +/- 12 x 10(3) vs 41 +/- 8 x 10(3) microm2. mean +/- SEM).     

Chlamydia pneumoniae infection accelerates hyperlipidemia induced atherosclerotic lesion development in C57BL/6J mice

Considerable evidence of an association between Chlamydia pneumoniae infections and cardiovascular disease has emerged. Animal models using genetically altered mice and hypercholesterolemic rabbits have shown a pathogenic role of C. pneumoniae in accelerating atherosclerotic plaque development. In the present study, we evaluated the effect of chronic C. pneumoniae infection on atherosclerosis in C57BL/6J mice, fed either a regular chow diet or a high fat, high cholesterol diet. Infected animals on an atherogenic diet developed significantly larger lesion areas compared with control mice at 18 weeks (2.5-fold increase; 4177+/-777 vs. 1650+/-808 microm(2); P<0.05) and 24 weeks of age (3.3-fold increase; 14139+/-4147 vs. 4298+/-869 microm(2); P<0.02). This study shows that chronic C. pneumoniae infection accelerates atherosclerotic lesion development in diet induced hypercholesterolemic mice, indicating that C. pneumoniae is a co-risk factor of hyperlipidemia in atherogenesis.     

Leptin deficiency suppresses progression of atherosclerosis in apoE-deficient mice

Both experimental and epidemiological studies suggest that leptin is one of the molecules responsible for accelerated atherosclerosis in obese humans. To confirm the notion, we studied whether leptin accelerates atherosclerosis in apoE(-/-) mice. Leptin deficient hyperlipidemic mice (ob/ob;apoE(-/-) mice) developed significantly less atherosclerosis than apoE(-/-) mice, when fed an atherogenic diet for 16 weeks from 8 weeks of age. Histological analysis revealed that most of the atherosclerotic lesions in ob/ob;apoE(-/-) mice remained as fatty streaks, while those in apoE(-/-) mice were mainly fibrous plaques. The decrease in atherosclerosis was not due to changes in the serum levels of cholesterol, TNF-alpha, or adiponectin. Exogenous leptin significantly increased atherosclerotic areas in apoE(-/-) mice, even though it decreased food intake and body weight. Our findings support the notion that leptin accelerates atherosclerosis.