Suplementação oral com Butirato de sódio reduz o desenvolvimento da aterosclerose e aumenta a estabilidade da placa em camundongos ApoE-/-

Abstract

Atherosclerosis is a major cardiovascular disease associated with high mortality worldwide. In the search for prevention or treatment of cardiovascular events, studies using nutrients has emerged strongly. Butyrate is produced in the body by the bacterial fermentation of fiber and undigested carbohydrates in the colon and is the main energy source for colonocytes. Butyrate has anti-inflammatory, anti-oxidants, anti-carcinogenic effects and other properties. Since atherosclerosis is a multifactorial disease in which inflammation and oxidative stress are important factors, anti-inflammatory and anti-oxidant properties of butyrate make it a promising nutrient for the study of its effect on atherogenesis. Therefore, the objective of this work was to study the effect of intake of butyrate in the development of atherosclerosis in apoprotein E-deficient mice (ApoE-/-). Male animals (6-8 weeks old) were fed a control diet or butyrate-supplemented diet (1%) for 10 weeks; control and Butyrate group, respectively. Before euthanasia, Oral Glucose Tolerance Test and Insulin Sensitivity Test were performed. Butyrate did not affect the lipid and glycemic profiles or oral glucose tolerance. However, the insulin sensitivity was improved in the butyrate group. Despite the absence of effect on serum cholesterol, there was a significant reduction of atherosclerosis in the aorta of the butyrate group. Although this reduction was not found at the aortic valve, this had less inflammatory molecules (VCAM1 and CCL2) in the lesions, as well as increased stability of the plate, since showed less matrix metalloproteinase-2 and increased collagen content. Lipid peroxidation in the liver of treated animals was also reduced, with lower concentrations of malondialdehyde and hydroperoxide associated with increased catalase activity. We also performed in vitro experiments to study the effect of pre-treatment of endothelial cells (EA.hy926) with butyrate. EA.hy926 cells were pre-icubated with butyrate for 2h and then stimulated with oxidized LDL. The pretreatment reduced production of proinflammatory molecules CCL2, VCAM1, TNF, IL-6 and IL-1, and increased secretion of anti-inflammatory cytokine IL-10. Butyrate also reduced the NF-kB activity and NADPH oxidase-p22phox expression. Therefore, the results suggest that the anti-atherogenic effects of butyrate may result from anti-inflammatory and antioxidant properties of this nutrient.