We-W42:1 Diet and inflammation

Wednesday, June 21, 2006: Workshop We-W42 Obesi~ and weight reduction (2nd part)

328 ]

We-W41:61 I M P A C T 1

O F DENDRITIC CELL LIFESPAN AND I M M U N O G E N I C I T Y O N ATHEROSCLEROSIS PROGRESSION

E. Gautier, T. Huby, B. Ouzilleau, J. Chapman, P. Lesnik. Inserm U551,

Hopital de la Pitid, Paris, France Introduction: Atherosclerosis is a chronic inflammatory disease involving immune system activation. Dendritic cells (DCs) axe major antigen-presenting cells that function to initiate immune response. The anti-apoptotic protein Bcl-2 acts as a molecular timer in DCs by regulating their lifespan and capacity to stimulate T cells. We investigated the impact of DC lifespan and immunogenicity on fatty streak development. Methods: We created a mouse model with hyperstimulatory DCs by overexpressing human Bcl-2 under the control of the CD1 l c promoter (hBcl-2 Tg). Atherosclerotic lesion area was compared in lethally-irradiated LDL-R-/mice transplanted with either wild-type (WT) or hBcl-2 Tg bone marrow cells. After a 4-week recovery, mice were fed a high fat diet (1.25% cholesterol) for 8 weeks. Results: hBcl2 expression in DCs derived from hBcl-2 Tg bone marrow was confirmed by intracellulax staining and was associated with enhanced DCs survival to growth factor deprivation compared to W T controls. After 8 weeks of diet, both groups of mice exhibited similar plasma lipid profiles and circulating leukocyte numbers. Analysis of splenocytes revealed increased proportions of activated T lymphocytes (CD3+ CD69+) in mice transplanted with hBcl-2 Tg bone marrow cells (p< 0.05). Preliminary analysis of aortic root lesions revealed a trend towards accelerated atherogenesis in LDL-R-/- mice transplanted with hBcl-2 Tg bone marrow cells. Conclusions: Increase in DC lifespan and immunogenic potential enhances activation of T lymphocytes which may in turn accelerate atherosclerosis. Funding: Fondation de France funded the study.

We-W41:7 ] THE EFFECTS OF 7BETA-HYDROXYCHOLESTEROL O N N K C E L L S IN PATIENTS WITH CORONARY ARTERY DISEASE. W. Li 1, X.M. Yuan 1 , L. Jonasson 2. 1Div of Experimental Pathology, Dpt of Neuroscience attd Locomotion, Facul~ of Health Sciences, Linkoping Universi~, Linkoping, Sweden." 2Div of Cardiology, Dpt of Medicine attd Care, Faculty of Health Sciences, Linkoping Universi~, Linkoping, Sweden Objectives: The loss of natural killer (NK) cells in patients with coronary artery disease (CAD) may be a result from cell death triggered by oxLDL. The toxicity of oxLDL has been associated with its oxidation products, oxysterols. In this study we investigated the effects of the oxysterol 7(,-hydroxycholesterol (7(,OH) on NK cells prepared from CAD patients and healthy subjects. Methods: Patients (mean age 61 years) with stable CAD but without any other chronic disease (n = 8) and matched healthy subjects (n = 8) were included. Pure NK cells were prepared from blood and exposed to 7(,OH for 18 h. The cells were analysed with respect to ROS production and apoptosis. Results: Exposure to 7V,OH overnight caused an increased ROS production in the NK cells that was significantly larger in patients ( > 6 fold increases) than in healthy ones (> 3 fold increases). The NK cell apoptosis induced by 7(,OH was much more pronounced in patients than in healthy subjects (6.8 fold vs. 3 fold, p < 0.05). Cultures of NK cells in complete medium resulted in a slightly increased ROS production (10%) and decreased cell viability (< 10%) that did not differ between patients and controls. Conclusions: Compared to NK cells from healthy subjects, NK cells from CAD patients were more susceptible to 7(,OH-induced cell loss. The proneness to apoptotic cell death ex vivo may be the consequence of a prolonged exposure to oxLDL in vivo. The data supports the hypothesis that circulating NK cells in CAD patients are lost due to oxidative stress. Funding: The work was supported from the Swedish Research Council and the Swedish Heart Lung Foundation.

We-W42

OBESITY AND WEIGHT REDUCTION

(2nd PART)

We-W42:1 ] D I E T A N D I N F L A M M A T I O N D. Giu21iano, K. Esposito. Division of Metabolic Diseases, Universi~ of

Naples SUN, Naples, Italy Reducing the incidence of coronary heart disease (CHD) with diet is possible. The main dietary strategies include adequate omega-3 fatty acids intake, reduction of saturated and trans-fats, and consumption of a diet high in fruits,

vegetables, nuts, and whole grains and low in refined grains. Each of these strategies may be associated with lower generation of inflammation. Although some epidemiological studies have shown an inverse correlation between dietary intake of fish or fish oil and circulating markers of inflammation, clinical trials have not yet confirmed these effects. A positive correlation between consumption of trans-fats, saturated fats and plasma biomaxkers of inflammation has been found, but the results of interventional studies are limited and not conclusive. Refined carbohydrates are highly processed, resulting in removal of fiber, vitamins, minerals, phytonutrients, and essential fatty acids. High intake of refined starches and sugars causes rapid swings in blood glucose and insulin levels, may increase hunger and elevate free fatty acids levels. Acute hyperglycemia in normal humans impairs endothelium dependent-vasodilation and reduces nitric oxide availability. Strictly related to this, is the emerging evidence that CHD may be more strongly related to post-load glucose hyperglycemia than to fasting hyperglycemia. Although the mechanisms underlying these associations axe not fully clear, recent data indicate that short-term acute hyperglycemia may increase circulating levels of flee radicals and proinflammatory cytokines, such as IL-6, IL-18, and TNF-a, providing a plausible explanation for the deleterious effects of rapid glycemic waves on vasculature. The role of overall dietary patterns in predicting long-term risk of CHD has recently been demonstrated. In practical terms, a prudent dietary pattern is characterized by the choice of foods that satisfy all the strategies so fax discussed for reducing CHD risk that is a higher intake of fruits, vegetables, legumes, whole grains, poultry, and fish. The Mediterranean-style diet can be considered a good example of a prudent dietary pattern. As the metabolic syndrome is highly prevalent and is a risk factor for CHD, interventions aimed at reducing its prevalence hopefully will contribute to decrease the burden of accompanying disease. Dietary patterns high in refined starches, sugar and saturated and trans-fatty acids, and poor in natural antioxidants and fiber from fruits, vegetables and whole grains, and in omega-3 fatty acids may cause an activation of the innate immune system, most likely by an excessive production of proinflammatory cytokines associated with a reduced production of anti-inflammatory cytokines. The whole diet approach seems particularly promising to reduce the inflammation associated with the metabolic syndrome. The choice of healthy sources of carbohydrate, fat and protein, associated with regular physical activity, and avoidance of smoking is critical to fighting the war against chronic disease. Western dietary patterns warm up inflammation, while prudent dietary patterns cool it down. References [1] Esposito K, Nappo F, Maffella R, et al. Inflammatory cytokine concentrations axe acutely increased by hyperglycemia in humans: role of oxidative stress. Circulation 2002; 106:2067-72 [2] Esposito K, Nappo F, Giugliano F, et al. Effect of dietary antioxidants on postprandial endothelial dysfunction induced by a high-fat meal in healthy subjects. A m J Clin Nutr 2003;77:139-43 [3] Esposito K, Marfella R, Ciotola M, et al. Effect of a Mediterranean-style diet on endothelial dysfunction and markers of vascular inflammation in the metabolic syndrome: a randomized trial. JAMA 2004;292:1440-6

DIETS AND PREVENTION OF IWe-W42:21 POPULAR CARDIOVASCULAR DISEASE F.F. Samaha. Universi~ of Petmsylvania Medical Center; PhilcMelphia, PA,

USA Obesity is associated with increased risk of cardiovascular disease and events, largely through its association with multiple metabolic factors associated with diabetes and metabolic syndrome, including elevated triglyceride levels, depressed HDL-C levels, high cholesterol, hypertension, and a pro-inflammatory state. This presentation will review the impact of several popular diets on cardiovascular risk, and focus on the role of both the amount and type of fat consumed in these diets. Since national guidelines began to recommend reducing total fat intake in 1988, the proportion of total calories derived from fat consumption decreased from 36.9% to 32.8% in men and from 36.1% to 32.8% in women. Roughly half of this overall decrease in fat consumption represented a decrease in saturated fat. Despite these reductions in fat intake, total caloric intake has increased, mostly attributable to increased carbohydrate intake. Given the concurrent increase in the prevalence of obesity, diabetes, and metabolic syndrome, there still remains debate on the amount and type of recommended dietary fat. Low fat diets are most popular in the U.S., based on the preponderance of data linking total fat intake to LDL-cholesterol (LDL-C) levels, and based on general recommendations from nutritional experts. However, there has been

XIV bztentational Symposium on Atherosclerosis, Rome, Italy, June 18-22, 2006