Title

Modulation of atherosclerosis and lipid metabolism by drug treatment and dietary interventions

Date of Completion

January 2009

Keywords

Health Sciences, Medicine and Surgery|Health Sciences, Nutrition

Degree

Ph.D.

Abstract

Cardiovascular diseases are the main cause of death in the United States. Most of treatments that are currently used are low-fat diet (LFD) and statins. However, alternatives have been proposed such as low-carbohydrate diets (LCD) and other drug treatments such as the use of inhibitors of secretory phospholipase A2 (i-sPLA2). Thus, in order to test whether they are an adequate alternative, two guinea pig studies were conducted. ^ The first study evaluated the effect of an i-sPLA2 on the prevention of atherosclerosis. The association of elevated levels of sPLA 2 in patients with cardiovascular diseases and their presence in atherosclerotic lesions suggest the participation of sPLA2 in this disease. Twenty-four guinea pigs were fed an atherogenic diet for twelve weeks. Half of them were treated with A-002, the i-sPLA2. The other animals were used as control. There was no difference on plasma lipids between groups, however, there was less inflammation (p<0.05) in aorta from the i-sPLA2 group. This group had a reduction in cholesterol in aorta compared with control group. Therefore, A-002 prevents atherosclerosis.^ The second study evaluated whether LCD prevent atherosclerosis. Since satiety positively affects the results of dietary interventions, the effects of LCD on appetite hormones were compared to those of LFD. Animals were subjected to LCD or LFD for 12 weeks. The LCD group gained while animals fed LFD lost weight. The amount of food intake was not different suggesting that food density and gastric distension played a role in satiety. There was no difference in leptin levels, which excludes the hypothesis of leptin resistance in the LCD group. However, the heavier animals that were fed LFD had impairment in insulin sensitivity, which was not observed in those fed LCD. Thus, the association between weight gain and insulin resistance seems to be dependent on high carbohydrate intake. ^ The effects of both LCD and LFD on atherosclerosis were also evaluated. LDL-cholesterol, aortic cholesterol, aorta oxLDL and inflammatory cytokines were lower in the LCD compared to the LFD group (p<0.05). Histological analyses supported these findings. In conclusion, both LCD and i-sPLA 2 are able to efficiently prevent atherosclerosis through different mechanisms. ^