Apolipoprotein E, periodontal disease and the risk for atherosclerosis: a review.

The association between cardiovascular and periodontal diseases is characterized by chronic inflammatory processes, with a high prevalence worldwide and complex genetic-environment interactions. Although apolipoprotein E4 (ApoE4), one of the isoforms coded by a polymorphic APOE gene, has been widely recognized as a risk factor for cardiovascular diseases and as an immunoinflammatory factor, less is known regarding how ApoE4 affects atherosclerosis in periodontitis patients. The aim of this review was to investigate the potential underlying mechanisms related to APOE4 that could increase the risk of periodontal disease and, ultimately, of atherosclerosis. There have only been a few studies addressing apoE polymorphisms in patients with chronic periodontitis. To date, no studies have been performed that have assessed how ApoE4 affects atherosclerotic disease in chronic periodontitis patients. Although clinical studies are warranted, experimental studies have consistently documented the presence of periodontal pathogens, which are usually found in the oral cavity and saliva, in the atherosclerotic plaques of ApoE-deficient mice. In addition, in this review, the potential role of the APOE4 allele as an example of antagonistic pleiotropy during human evolution and its relation to oral health is discussed.

Wheat gluten intake increases weight gain and adiposity associated with reduced thermogenesis and energy expenditure in an animal model of obesity.

BACKGROUND/OBJECTIVES: The association between gluten and body weight is inconsistent. Previously, we showed that a gluten-free diet reduces weight gain without changing food intake in mice fed high-fat diets. In the present study, we investigated the effects of gluten intake on fat metabolism, thermogenesis and energy expenditure in mice fed a standard or high-fat diet. METHODS: Mice were fed four different experimental diets during 8 weeks: a control-standard diet (CD), a CD added with 4.5% of wheat gluten (CD-G), a high-fat diet (HFD) and a HFD added with 4.5% of wheat gluten (HFD-G). After 8 weeks, the mice received (99m)Tc-radiolabeled gluten orally to study gluten absorption and biodistribution or they underwent indirect calorimetry. After killing, subcutaneous and brown adipose tissues (SAT and BAT) were collected to assess thermogenesis-related protein expression. Lipid metabolism was studied in adipocyte cultures from the four groups. RESULTS: Despite having had the same energy intake, CD-G and HFD-G mice exhibited increased body weight and fat deposits compared with their respective controls. (99m)Tc-GLU or its peptides were detected in the blood, liver and visceral adipose tissue, suggesting that gluten can even reach extraintestinal organs. Uncoupling protein-1 expression was reduced in the BAT of HFD-G and in the SAT of CD-G and HFD-G mice. Indirect calorimetry showed lower oxygen volume consumption in CD-G and HFD-G groups compared with their controls. In HFD mice, daily energy expenditure was reduced with gluten intake. Gluten also reduced adiponectin, peroxisome proliferator-activated receptor (PPAR)-α and PPARγ and hormone-sensitive lipase in cultures of isolated adipocytes from HFD mice, whereas in the CD-G group, gluten intake increased interleukin-6 expression and tended to increase that of tumor necrosis factor. CONCLUSIONS: Wheat gluten promotes weight gain in animals on both HFD and CD, partly by reducing the thermogenic capacity of adipose tissues.

Combined swimming and soybean intake reduce early atherosclerotic lesions and serum oxidative stress in mice.

AIM: Physical exercise and soybean intake reduced oxidative stress and atherosclerosis. However, the associated effects of both interventions have not been yet investigated. Thus, we aimed to evaluate the combined effects of swimming and soybean intake on lipid profile, oxidative stress and atherogenesis. METHODS: Ten-week-old male Low-Density Lipoprotein Receptor Knockout mice were divided into 4 groups (N.=8 for each group): control diet without swimming; control diet with swimming; soybean rich diet without swimming and soybean rich diet with swimming. Diets were based on American Institute of Nutrition 93 Growth. The diet of soybean groups was made by soybean extract contained isoflavones. The animals in the exercise groups underwent a 6-week swimming program five times per week. Plasma lipid profile was determined using enzymatic kits. Oxidative stress was measured by thiobarbituric acid reactive substances, hydroperoxide and the lipid oxidation resistance determinations. Atherosclerotic lesions were calculated by morphometry. RESULTS: Soybean intake increased high density lipoprotein cholesterol. Moreover, soybean and exercise individually reduced hepatic oxidative stress and atherogenesis in aortic valve. No additional effect was seen in soybean+exercise group. However, the association of soybean and exercise reduced the percentage of lesion area in arch, thoracic and abdominal aorta and increased serum antioxidant potential. CONCLUSION: Soybean intake and swimming are beneficial in reducing atherosclerosis besides improving lipid profile and reducing lipid peroxidation. The association of soybean and swimming aggregates beneficial effects in serum antioxidant potential and in aorta lesion.

Butyrate impairs atherogenesis by reducing plaque inflammation and vulnerability and decreasing NFκB activation.

BACKGROUND & AIMS: Butyrate is a four-carbon fatty acid that presents anti-inflammatory, anti-oxidative and apoptotic properties in colon and several cell lines. Because atherosclerosis has important oxidative and inflammatory components, butyrate could reduce oxidation and inflammation, impairing atherogenesis. We evaluated the effects of butyrate supplementation of butyrate on atherosclerosis and its mechanisms of action. METHODS AND RESULTS: ApoE knockout mice were fed on chow diet or 1% butyrate-supplemented chow diet (Butyrate) for 10 weeks to assess atherosclerosis lesions area and inflammatory status. Macrophage and endothelial cells were also pretreated with butyrate (0.5 mM) for 2 h before oxLDL stimulation to study oxLDL uptake and pro and anti-inflammatory cytokine production. Butyrate reduced atherosclerosis in the aorta by 50%. In the aortic valve, butyrate reduced CCL2, VCAM1 and MMP2 productions in the lesion site, resulting in a lower migration of macrophage and increased collagen depositions in the lesion and plaque stability. When EA.hy926 cells were pretreated with butyrate, oxLDL uptake, CD36, VCAM1, CCL2 TNF, IL1ß and IL6 productions were reduced, whereas IL10 production was increased. These effects were accompanied by a lower activation of NFκB due to a lower nuclear translocation of the p65 subunit. CONCLUSION: Oral butyrate is able to slow the progression of atherosclerosis by reducing adhesion and migration of macrophages and increasing plaque stability. These actions are linked to the reduction of CD36 in macrophages and endothelial cells, decreased pro-inflammatory cytokines and lower activation of NFκB all of these data support a possible role for butyrate as an atheroprotective agent.

Reciprocal interference of experimental dyslipidemia and food allergy in the evolution of both diseases.

Background. Food allergies have been shown to reduce serum triacylglycerol, glucose, cholesterol, and free fatty acid levels in mice. In turn, dyslipidemias, especially dyslipidemias presenting with low levels of HDL cholesterol, are important risk factors for the development of atherosclerosis. However, the consequences of food allergies on dyslipidemia and atherosclerosis have not been fully investigated. Methods. Food allergy was induced using an egg white solution (EWS) in ovalbumin- (OVA-) sensitized C57BL/6 and low-density lipoprotein receptor knockout mice (LDLr(-/-)) for 5 weeks and was confirmed by the high production of anti-OVA IgE and IgG1 antibodies in both mouse strains. Results. The allergic C57BL/6 mice exhibited EWS aversion that was associated with less visceral fat and high levels of anti-Ova IgE antibodies after 5 weeks of EWS intake compared to controls. However, LDLr(-/-) allergic mice showed reduced anti-Ova IgE levels that were similar to the nonsensitized group. The LDLr(-/-) allergic mice also demonstrated a reversal of food aversion and sustained visceral fat after 5 weeks of allergy. Although HDL cholesterol levels were reduced in both sensitized mouse strains, lipid deposition in thoracic and abdominal aorta as well as area and composition of atherosclerotic plaques as unaffected by chronic ingestion of EWS. Conclusion. LDLr(-/-) mice develop an attenuated food allergy, as they showed a reversal of food aversion and lower IgE production after 5 weeks of induced allergy. The development of atherosclerosis, in turn, was not accelerated in the allergic LDLr(-/-) group despite the more atherogenic lipid profile.

Paradoxical effect of a pequi oil-rich diet on the development of atherosclerosis: balance between antioxidant and hyperlipidemic properties

Pequi is the fruit of Caryocar brasiliense and its oil has a high concentration of monounsaturated and saturated fatty acids, which are anti- and pro-atherogenic agents, respectively, and of carotenoids, which give it antioxidant properties. Our objective was to study the effect of the intake of a cholesterol-rich diet supplemented with pequi oil, compared to the same diet containing soybean oil, on atherosclerosis development, and oxidative stress in atherosclerosis-susceptible LDL receptor-deficient mice (LDLr-/-, C57BL/6-background). Female mice were fed a cholesterol-rich diet containing 7% soybean oil (Soybean group, N = 12) or 7% pequi oil (Pequi group, N = 12) for 6 weeks. The Pequi group presented a more atherogenic lipid profile and more advanced atherosclerotic lesions in the aortic root compared to the Soybean group. However, the Pequi group presented a less advanced lesion in the aorta than the Soybean group and showed lower lipid peroxidation (Soybean group: 50.2 ± 7.1; Pequi group: 30.0 ± 4.8 µmol MDA/mg protein) and anti-oxidized LDL autoantibodies (Soybean group: 35.7 ± 9.4; Pequi group: 15.6 ± 3.7 arbitrary units). Peritoneal macrophages from the Pequi group stimulated with zymosan showed a reduction in the release of reactive oxygen species compared to the Soybean group. Our data suggest that a pequi oil-rich diet slows atherogenesis in the initial stages, possibly due to its antioxidant activity. However, the increase of serum cholesterol induces a more prominent LDL migration toward the intimae of arteries, increasing the advanced atherosclerotic plaque. In conclusion, pequi oil associated with an atherogenic diet worsens the lipid profile and accelerates the formation of advanced atherosclerotic lesions despite its antioxidant action.

Paradoxical effect of a pequi oil-rich diet on the development of atherosclerosis: balance between antioxidant and hyperlipidemic properties.

Pequi is the fruit of Caryocar brasiliense and its oil has a high concentration of monounsaturated and saturated fatty acids, which are anti- and pro-atherogenic agents, respectively, and of carotenoids, which give it antioxidant properties. Our objective was to study the effect of the intake of a cholesterol-rich diet supplemented with pequi oil, compared to the same diet containing soybean oil, on atherosclerosis development, and oxidative stress in atherosclerosis-susceptible LDL receptor-deficient mice (LDLr(-/-), C57BL/6-background). Female mice were fed a cholesterol-rich diet containing 7% soybean oil (Soybean group, N = 12) or 7% pequi oil (Pequi group, N = 12) for 6 weeks. The Pequi group presented a more atherogenic lipid profile and more advanced atherosclerotic lesions in the aortic root compared to the Soybean group. However, the Pequi group presented a less advanced lesion in the aorta than the Soybean group and showed lower lipid peroxidation (Soybean group: 50.2 ± 7.1; Pequi group: 30.0 ± 4.8 µmol MDA/mg protein) and anti-oxidized LDL autoantibodies (Soybean group: 35.7 ± 9.4; Pequi group: 15.6 ± 3.7 arbitrary units). Peritoneal macrophages from the Pequi group stimulated with zymosan showed a reduction in the release of reactive oxygen species compared to the Soybean group. Our data suggest that a pequi oil-rich diet slows atherogenesis in the initial stages, possibly due to its antioxidant activity. However, the increase of serum cholesterol induces a more prominent LDL migration toward the intimae of arteries, increasing the advanced atherosclerotic plaque. In conclusion, pequi oil associated with an atherogenic diet worsens the lipid profile and accelerates the formation of advanced atherosclerotic lesions despite its antioxidant action.

Decreased production of neuronal NOS-derived hydrogen peroxide contributes to endothelial dysfunction in atherosclerosis.

BACKGROUND AND PURPOSE: Reduced NO availability has been described as a key mechanism responsible for endothelial dysfunction in atherosclerosis. We previously reported that neuronal NOS (nNOS)-derived H(2)O(2) is an important endothelium-derived relaxant factor in the mouse aorta. The role of H(2)O(2) and nNOS in endothelial dysfunction in atherosclerosis remains undetermined. We hypothesized that a decrease in nNOS-derived H(2)O(2) contributes to the impaired vasodilatation in apolipoprotein E-deficient mice (ApoE(-/-)). EXPERIMENTAL APPROACH: Changes in isometric tension were recorded on a myograph; simultaneously, NO and H(2)O(2) were measured using carbon microsensors. Antisense oligodeoxynucleotides were used to knockdown eNOS and nNOS in vivo. Western blot and confocal microscopy were used to analyse the expression and localization of NOS isoforms. KEY RESULTS: Aortas from ApoE(-/-) mice showed impaired vasodilatation paralleled by decreased NO and H(2)O(2) production. Inhibition of nNOS with L-Arg(NO2) -L-Dbu, knockdown of nNOS and catalase, which decomposes H(2)O(2) into oxygen and water, decreased ACh-induced relaxation by half, produced a small diminution of NO production and abolished H(2)O(2) in wild-type animals, but had no effect in ApoE(-/-) mice. Confocal microscopy showed increased nNOS immunostaining in endothelial cells of ApoE(-/-) mice. However, ACh stimulation of vessels resulted in less phosphorylation on Ser852 in ApoE(-/-) mice. CONCLUSIONS AND IMPLICATIONS: Our data show that endothelial nNOS-derived H(2)O(2) production is impaired and contributes to endothelial dysfunction in ApoE(-/-) aorta. The present study provides a new mechanism for endothelial dysfunction in atherosclerosis and may represent a novel target to elaborate the therapeutic strategy for vascular atherosclerosis.

Association of apoliprotein E polymorphisms and metabolic syndrome in subjects with extreme obesity.

BACKGROUND: Obesity has been linked to metabolic syndrome (MS), which increases the risk of cardiovascular disease (CVD). Polymorphisms of Apolipoprotein E have also been associated with increased CVD risk. Therefore, this study investigated the association between MS and Apo E polymorphisms. METHODS: We measured anthropometric and biochemical variables and determined the Apo E genotype of 147 grade III obese patients. RESULTS: The percentage of female subjects was 86.4%. The mean age and BMI of the subjects were 41 years and 53.5 kg/m(2), respectively. MS had been diagnosed in 79% of the subjects. The proportions of those exhibiting MS risk factors were as follows: 100% had a high BMI, 80% had hypertension, 65% had low levels of high-density lipoprotein (HDL), 38% had diabetes, and 39% had hypertriglyceridemia. We found five genotypes for which the allelic distribution was different in the MS group compared to the general population. The ε4 allele was more frequent in the group with neither MS nor hypertension. CONCLUSIONS: The morbidly obese patients exhibited a higher incidence of MS and a different allelic distribution when compared with other populations. The ε4 allele was associated with the absence of MS and hypertension.

Effect of Lactobacillus delbrueckii on cholesterol metabolism in germ-free mice and on atherogenesis in apolipoprotein E knock-out mice.

Elevated blood cholesterol is an important risk factor associated with atherosclerosis and coronary heart disease. Several studies have reported a decrease in serum cholesterol during the consumption of large doses of fermented dairy products or lactobacillus strains. The proposed mechanism for this effect is the removal or assimilation of intestinal cholesterol by the bacteria, reducing cholesterol absorption. Although this effect was demonstrated in vitro, its relevance in vivo is still controversial. Furthermore, few studies have investigated the role of lactobacilli in atherogenesis. The aim of the present study was to determine the effect of Lactobacillus delbrueckii on cholesterol metabolism in germ-free mice and the possible hypocholesterolemic and antiatherogenic action of these bacteria using atherosclerosis-prone apolipoprotein E (apo E) knock-out (KO) mice. For this purpose, Swiss/NIH germ-free mice were monoassociated with L. delbrueckii and fed a hypercholesterolemic diet for four weeks. In addition, apo E KO mice were fed a normal chow diet and treated with L. delbrueckii for 6 weeks. There was a reduction in cholesterol excretion in germ-free mice, which was not associated with changes in blood or liver cholesterol concentration. In apo E KO mice, no effect of L. delbrueckii was detected in blood, liver or fecal cholesterol. The atherosclerotic lesion in the aorta was also similar in mice receiving or not these bacteria. In conclusion, these results suggest that, although L. delbrueckii treatment was able to reduce cholesterol excretion in germ-free mice, no hypocholesterolemic or antiatherogenic effect was observed in apo E KO mice.

Effect of Lactobacillus delbrueckii on cholesterol metabolism in germ-free mice and on atherogenesis in apolipoprotein E knock-out mice

Elevated blood cholesterol is an important risk factor associated with atherosclerosis and coronary heart disease. Several studies have reported a decrease in serum cholesterol during the consumption of large doses of fermented dairy products or lactobacillus strains. The proposed mechanism for this effect is the removal or assimilation of intestinal cholesterol by the bacteria, reducing cholesterol absorption. Although this effect was demonstrated in vitro, its relevance in vivo is still controversial. Furthermore, few studies have investigated the role of lactobacilli in atherogenesis. The aim of the present study was to determine the effect of Lactobacillus delbrueckii on cholesterol metabolism in germ-free mice and the possible hypocholesterolemic and antiatherogenic action of these bacteria using atherosclerosis-prone apolipoprotein E (apo E) knock-out (KO) mice. For this purpose, Swiss/NIH germ-free mice were monoassociated with L. delbrueckii and fed a hypercholesterolemic diet for four weeks. In addition, apo E KO mice were fed a normal chow diet and treated with L. delbrueckii for 6 weeks. There was a reduction in cholesterol excretion in germ-free mice, which was not associated with changes in blood or liver cholesterol concentration. In apo E KO mice, no effect of L. delbrueckii was detected in blood, liver or fecal cholesterol. The atherosclerotic lesion in the aorta was also similar in mice receiving or not these bacteria. In conclusion, these results suggest that, although L. delbrueckii treatment was able to reduce cholesterol excretion in germ-free mice, no hypocholesterolemic or antiatherogenic effect was observed in apo E KO mice.

Bacteria recovered from dental pulp induce apoptosis of lymph node cells.

Apoptosis is critical in the pathogenesis of several infectious diseases. The induction of apoptosis was assessed in mouse lymph node cells by four bacteria recovered from infected human dental pulp: Gemella morbillorum, Clostridium butyricum, Fusobacterium nucleatum and Bifidobacterium adolescentis. Smaller lymph nodes and smaller numbers of cells were observed after experimental dental pulp infection with C. butyricum, suggesting that this bacterium induces cell death. Apoptosis was evaluated by determination of cell ploidy and detection of DNA degradation in cells cultured with killed bacteria. Paraformaldehyde-killed C. butyricum and heat-killed G. morbillorum induced substantial cell death, while F. nucleatum and B. adolescentis induced cell death at lower levels. No bacterial preparations induced apoptosis in cells from mice genetically deficient for tumour necrosis factor receptor p55 (TNFRp55), implicating this receptor directly or indirectly as a mediator in the process. It was concluded that apoptosis may be induced during periapical lesions of pulpal origin.

Butyrate increases apoptosis induced by different antineoplastic drugs in monocytic leukemia cells.

BACKGROUND: Apoptosis is an essential form of cell death, the failure of which can lead to cancer development. Cancer including leukemia is usually treated with chemotherapeutic drugs that can be effective, but frequently problems are encountered that impair the success of the treatment. Butyrate is a short-chain fatty acid that can have many effects on different cells, including apoptosis. METHODS: The effect of a combination treatment with butyrate and antineoplastic agents Ara-C, etoposide and vincristine is evaluate on the leukemic cell line THP-1. RESULTS: We show that butyrate increased apoptosis induced by the three agents as seen by measurement of DNA content, annexin exposure and morphological characteristics. We also demonstrate that the process of apoptosis induced by butyrate and chemotherapeutic drugs involves the participation of caspases and induced activation of caspase-3, -8 and -9. CONCLUSIONS: We believe that butyrate could be a promising therapeutic agent for the treatment of leukemia in combination with other antineoplastic drugs.

A model of chronic IgE-mediated food allergy in ovalbumin-sensitized mice.

Food allergy is most frequently the result of IgE-mediated hypersensitivity reactions. Here, we describe a chronic model in which some of the intestinal and systemic consequences of continuous egg white solution ingestion by ovalbumin-sensitized eight-week-old BALB/c mice, 6 animals per group, of both sexes, were investigated. There was a 20% loss of body weight that began one week after antigen exposure and persisted throughout the experiment (3 weeks). The sensitization procedure induced the production of anti-ovalbumin IgG1 and IgE, which were enhanced by oral antigen exposure (129% for IgG1 and 164% for IgE, compared to sensitization values). Intestinal changes were determined by jejunum edema at 6 h (45% Evans blue extravasation) and by a significant eosinophil infiltration with a peak at 48 h. By day 21 of continuous antigen exposure, histological findings were mild, with mast cell hyperplasia (100%) and increased mucus production (483%). Altogether, our data clearly demonstrate that, although immune stimulation was persistently occurring in response to continuous oral antigen exposure, regulatory mechanisms were occurring in the intestinal mucosa, preventing overt pathology. The experimental model described here reproduces the clinical and pathological changes of mild chronic food allergy and may be useful for mechanistic studies of this common clinical condition.

A model of chronic IgE-mediated food allergy in ovalbumin-sensitized mice

Food allergy is most frequently the result of IgE-mediated hypersensitivity reactions. Here, we describe a chronic model in which some of the intestinal and systemic consequences of continuous egg white solution ingestion by ovalbumin-sensitized eight-week-old BALB/c mice, 6 animals per group, of both sexes, were investigated. There was a 20 percent loss of body weight that began one week after antigen exposure and persisted throughout the experiment (3 weeks). The sensitization procedure induced the production of anti-ovalbumin IgG1 and IgE, which were enhanced by oral antigen exposure (129 percent for IgG1 and 164 percent for IgE, compared to sensitization values). Intestinal changes were determined by jejunum edema at 6 h (45 percent Evans blue extravasation) and by a significant eosinophil infiltration with a peak at 48 h. By day 21 of continuous antigen exposure, histological findings were mild, with mast cell hyperplasia (100 percent) and increased mucus production (483 percent). Altogether, our data clearly demonstrate that, although immune stimulation was persistently occurring in response to continuous oral antigen exposure, regulatory mechanisms were occurring in the intestinal mucosa, preventing overt pathology. The experimental model described here reproduces the clinical and pathological changes of mild chronic food allergy and may be useful for mechanistic studies of this common clinical condition.

Butyrate induces apoptosis in murine macrophages via caspase-3, but independent of autocrine synthesis of tumor necrosis factor and nitric oxide.

We demonstrated that 4 mM butyrate induces apoptosis in murine peritoneal macrophages in a dose- and time-dependent manner as indicated by studies of cell viability, flow cytometric analysis of annexin-V binding, DNA ladder pattern and the determination of hypodiploid DNA content. The activity of caspase-3 was enhanced during macrophage apoptosis induced by butyrate and the caspase inhibitor z-VAD-FMK (100 microM) inhibited the butyrate effect, indicating the major role of the caspase cascade in the process. The levels of butyrate-induced apoptosis in macrophages were enhanced by co-treatment with 1 microg/ml bacterial lipopolysaccharide (LPS). However, our data indicate that apoptosis induced by butyrate and LPS involves different mechanisms. Thus, LPS-induced apoptosis was only observed when macrophages were primed with IFN-gamma and was partially dependent on iNOS, TNFR1 and IRF-1 functions as determined in experiments employing macrophages from various knockout mice. In contrast, butyrate-induced macrophage apoptosis was highly independent of IFN-gamma priming and of iNOS, TNFR1 and IRF-1 functions.

Butyrate induces apoptosis in murine macrophages via caspase-3, but independent of autocrine synthesis of tumor necrosis factor and nitric oxide

We demonstrated that 4 mM butyrate induces apoptosis in murine peritoneal macrophages in a dose- and time-dependent manner as indicated by studies of cell viability, flow cytometric analysis of annexin-V binding, DNA ladder pattern and the determination of hypodiploid DNA content. The activity of caspase-3 was enhanced during macrophage apoptosis induced by butyrate and the caspase inhibitor z-VAD-FMK (100 æM) inhibited the butyrate effect, indicating the major role of the caspase cascade in the process. The levels of butyrate-induced apoptosis in macrophages were enhanced by co-treatment with 1 æg/ml bacterial lipopolysaccharide (LPS). However, our data indicate that apoptosis induced by butyrate and LPS involves different mechanisms. Thus, LPS-induced apoptosis was only observed when macrophages were primed with IFN-gamma and was partially dependent on iNOS, TNFR1 and IRF-1 functions as determined in experiments employing macrophages from various knockout mice. In contrast, butyrate-induced macrophage apoptosis was highly independent of IFN-gamma priming and of iNOS, TNFR1 and IRF-1 functions

Influences of alpha-tocopherol on cholesterol metabolism and fatty streak development in apolipoprotein E-deficient mice fed an atherogenic diet

Although the role of oxidized lipoproteins is well known in atherogenesis, the role of vitamin E supplementation is still controversial. There is also little information about cholesterol metabolism (hepatic concentration and fecal excretion) in the new models of atherosclerosis. In the present study, we evaluated the effect of moderate vitamin E supplementation on cholesterol metabolism and atherogenesis in apolipoprotein E (apo E)-deficient mice. Apo E-deficient mice were fed an atherogenic diet containing 40 or 400 mg/kg of alpha-tocopherol acetate for 6 weeks. Total cholesterol in serum and liver and 3-OH-alpha-sterols in feces, and fecal excretion of bile acids were determined and histological analyses of aortic lesion were performed. A vitamin E-rich diet did not affect body weight, food intake or serum cholesterol. Serum and hepatic concentrations of cholesterol as well as sterol concentration in feces were similar in both groups. However, when compared to controls, the alpha-tocopherol-treated mice showed a reduction of about 60 percent in the atherosclerotic lesions when both the sum of lesion areas and the average of the largest lesion area were considered. These results demonstrate that supplementation of moderate doses of alpha-tocopherol was able to slow atherogenesis in apo E-deficient mice and to reduce atherogenic lipoproteins without modifying the hepatic pool or fecal excretion of cholesterol and bile acids

Influences of alpha-tocopherol on cholesterol metabolism and fatty streak development in apolipoprotein E-deficient mice fed an atherogenic diet.

Although the role of oxidized lipoproteins is well known in atherogenesis, the role of vitamin E supplementation is still controversial. There is also little information about cholesterol metabolism (hepatic concentration and fecal excretion) in the new models of atherosclerosis. In the present study, we evaluated the effect of moderate vitamin E supplementation on cholesterol metabolism and atherogenesis in apolipoprotein E (apo E)-deficient mice. Apo E-deficient mice were fed an atherogenic diet containing 40 or 400 mg/kg of alpha-tocopherol acetate for 6 weeks. Total cholesterol in serum and liver and 3-OH-alpha-sterols in feces, and fecal excretion of bile acids were determined and histological analyses of aortic lesion were performed. A vitamin E-rich diet did not affect body weight, food intake or serum cholesterol. Serum and hepatic concentrations of cholesterol as well as sterol concentration in feces were similar in both groups. However, when compared to controls, the alpha-tocopherol-treated mice showed a reduction of about 60% in the atherosclerotic lesions when both the sum of lesion areas and the average of the largest lesion area were considered. These results demonstrate that supplementation of moderate doses of alpha-tocopherol was able to slow atherogenesis in apo E-deficient mice and to reduce atherogenic lipoproteins without modifying the hepatic pool or fecal excretion of cholesterol and bile acids.

Gelatin intake increases the atheroma formation in apoE knock out mice.

The effect of gelatin ingestion on cholesterol metabolism and on atheroma formation was evaluated in both wild type (n=14) and apoprotein E (apoE) knock out (apoE(-/-)) (n=20) C57BL/6 7-week-old mice. Animals were fed a cholesterol-free isoproteic semi-purified diet containing 20% of casein (control diet) or 10% of casein plus 10% of gelatin (gel diet) for 8 weeks. In wild type mice, dietary gelatin caused a reduction in the serum triacylglycerols levels associated with an increase in the fecal excretion. No difference in blood cholesterol was seen at the sixth week of experiment. At the eighth week of experiment, there was a modest but significant reduction of serum total and high density lipoprotein (HDL) cholesterol in apoE(-/-) mice fed on gel diet compared to the control. Total cholesterol/HDL cholesterol ratio was 2-fold higher in the gel group than that seen in the control group (14.39 and 7.84, respectively). Histological analyzes showed a 2.2-fold increase in the dimension of the atherosclerotic plaques in the proximal aorta in apoE(-/-) mice fed on a gel diet compared to those fed on a control diet. The gel diet also promoted a reduction in the fecal excretion of bile acids. Hepatic cholesterol was similar in both groups. In conclusion, although gelatin reduced total serum cholesterol, this reduction was associated to a decrease of HDL cholesterol and consequent increase of total cholesterol/HDL cholesterol ratio, resulting in an acceleration of atherogenesis.