Impact of fatty acids in atherosclerotic lesion formation and inflammation.

摘要

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in the United States and other developed countries, and more recently of major concern in developing countries. Diet is a key component for CVD risk reduction. Type of fatty acids is an important dietary factor related to CVD. The major subclasses of dietary fatty acids include saturated fatty acids (SFA), monounsaturated fatty acids (MUFA) and polyunsaturated fatty acids (PUFA). The first part of the thesis research was the animal study designed to determine the effect of low SFA and cholesterol (semipurified, 4% fat and 0.02% cholesterol, w/w) and high SFA and cholesterol (atherogenic, 20% fat and 0.2% cholesterol, w/w) diets on aortic lesion formation and inflammatory response in low density lipoprotein receptor null (LDLr-/-) mice. After 32 weeks of feeding, aortic total cholesterol (TC), free cholesterol and cholesteryl ester (CE) were 5.5 (P0.001), 4.9 (P0.001) and 6.4 (P0.001) fold higher, respectively, in mice fed the atherogenic diet compared to the semipurified diet. Mice fed the atherogenic diet had a higher aortic macrophage (M&phis;) content, higher serum concentrations of non high density lipoprotein-cholesterol (non HDL-C, P0.001) and TC/HDL-C ratio (P0.01), as well as higher plasma concentrations of monocyte chemoattractant protein-1 (MCP-1, P0.01), tumor necrosis factor alpha (TNFalpha, P0.01) and interleukin-6 (IL-6, P0.001), compared to mice fed the semipurified diet. Elicited peritoneal M&phis; TC (P0.01) and CE (P0.001) accumulation were significantly higher in the atherogenic relative to semipurified diet fed mice. MCP-1 mRNA level (P0.05) and secretion (P0.01) were significantly higher in the elicited peritoneal M&phis; isolated from the atherogenic compared to semipurified diet fed mice. ATP-binding cassette A1 (ABCA1) mRNA and protein (both P0.01) levels showed a similar pattern, whereas there was no significant effect of the dietary perturbation on the expression of CD36, M&phis; scavenger receptor 1 (MSR1), scavenger receptor B1 (SR-B1), TNFalpha and IL-6 in elicited peritoneal M&phis;. The second part of the animal study was designed to address the effect of different ratios of dietary omega (o)-6 PUFA to eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on atherogenesis and the inflammatory response. Mice were fed high SFA and cholesterol (HSF) diets without EPA and DHA (HSF o-6), or with o-6:EPA+DHA ratios of 20:1 (HSF R=20:1), 4:1 (HSF R=4:1) and 1:1 (HSF R=1:1) for 32 weeks. Mice fed lower o-6:EPA+DHA ratio diets had lower concentrations of serum non HDL-C (P0.05) as well as lower plasma concentrations of IL-6 (P0.05) compared to mice fed the HSF o-6 diet. Aortic TC content was 24% (p=0.07) lower in HSF R=1:1 compared to HSF o-6 diet fed mice. Elicited peritoneal M&phis; TC and CE accumulation was 25% (P0.05) and 38% (P0.01) lower, respectively, in HSF R=1:1 relative to HSF o-6 diet fed mice. mRNA levels (P0.05) and secretion of MCP-1 (P0.05) were significantly lower in elicited peritoneal M&phis; isolated from HSF R=1:1 compared to HSF o-6 diet fed mice. In elicited peritoneal M&phis; mRNA and protein levels of ABCA1 and mRNA level of TNFalpha (all P0.05) showed a similar significantly lower trend, whereas there was no significant effect of dietary o-6:EPA+DHA ratios on CD36, MSR1, SR-B1 or IL-6. These data suggest that the diet with lower ratio of o-6:EPA+DHA compared to the diet with a higher ratio resulted in less M&phis; cholesterol accumulation and inflammatory response, aortic M&phis; deposition, and blood concentrations of lipids and inflammatory factors, which in turn were associated with less aortic lesion formation in LDLr-/- mice. In the last part of the thesis, M&phis; differentiated from human monocyte cell line THP-1 were used as a model to assess the effect of major dietary o-3 PUFA (EPA and DHA), o-6 PUFA (linoleic