Dietary n-3 polyunsaturated fatty acids prevent the development of atherosclerotic lesions in mice. Modulation of macrophage secretory activities.

Abstract

We examined the effects of dietary n-3 polyunsaturated and saturated fatty acids on the development of the atherogenic process in mice and on the macrophage ability to secrete several effector molecules that may be involved in the atherogenic process. The secretion of inflammatory proteins such as tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta) and the production of lipoprotein lipase (LPL), nitrogen oxide (NO2), and prostaglandin E2 (PGE2) were evaluated in peritoneal macrophages isolated from atherosclerosis-susceptible C57BL/6J mice. The mice were assigned at random to three experimental groups: the first group was fed a semi-defined control diet (control diet); the second group was maintained on the control diet supplemented with 10% menhaden oil (menhaden diet); and the third group received the control diet supplemented with 10% palm oil plus 2% cholesterol (saturated fat diet). Macrophages derived from mice fed the menhaden diet showed a suppression of their basal TNF-alpha mRNA expression and production. They also presented a dramatically decreased ability to express TNF-alpha and IL-1 beta mRNAs in response to exposure to lipopolysaccharide (LPS) compared with the macrophages from the control group. LPL mRNA and protein expression were downregulated after 6 and 15 weeks of menhaden-diet feeding. Significantly higher NO2 production in response to interferon gamma was found, both after 6 and 15 weeks of diet feeding, in the menhaden group compared with the control group. In addition, prostaglandin production and macrophage tumoricidal activity in response to LPS were decreased in this group compared with the control group. Macrophages derived from the saturated fat group did not show any significant alterations in TNF-alpha, LPL, NO2, or PGE2 secretion compared with controls. Interestingly, we observed a progressive increase of the LPS-induced IL-1 beta gene expression and secretion among macrophages harvested from mice receiving the dietary supplement of saturated fatty acids. At 6 and 15 weeks histologic examination of the atherosclerotic lesions did not reveal any important lesions in the control and menhaden groups, whereas a gradual development of fatty streaks was observed in the menhaden experimental diets for 10 additional weeks resulted in a major development of lesions in the control group, whereas only slight lesions were observed in the menhaden group.(ABSTRACT TRUNCATED AT 400 WORDS)

Direct Regulatory Effect of Fatty Acids on Macrophage Lipoprotein Lipase

“…n-3 FA may favorably affect the atherogenic process by reducing the secretion of proatherogenic cytokines by Mo. In accordance with our previous observation showing a reduction in LPL mRNA levels in Mo isolated from mice fed a fish oil-enriched diet (60) we found that incubation of Mo with n-3 FA for 24 h decreases Mo LPL gene expression and that prolonged incubation (48 h) of Mo with this FA reduces Mo LPL secretion (data not shown). Overall, these data suggest that a relative reduction in Mo LPL production may contribute to the cardioprotective effect of n-3 FA.…”

The α-linolenic acid content of flaxseed can prevent the atherogenic effects of dietary trans fat

“…This conclusion would be consistent with other studies investigating the effects of ALA on cardiovascular disease. Epidemiological, randomized clinical trials and experimental investigations suggest that ALA may be anti-atherogenic via a host of cardioprotective actions (15,16,37,43,45). It has been suggested to reduce circulating cholesterol levels; it may act as an antiinflammatory, anti-aggregatory, hypotensive, and anti-arrhythmic agent; and it can inhibit the proliferative processes that occur in cells found in the atherosclerotic vessel wall (1,2,10,15,16,31,37,43,45).…”

Dietary n-3 LCPUFA from fish oil but not α-linolenic acid-derived LCPUFA confers atheroprotection in mice

“…It has been shown that fl axseed lignan and secoisolariciresinol diglucoside (SDG) may exert antioxidant and hypotensive activity and may provide benefi cial effects on infl ammatory mediators [interleukin (IL)-1 ␤ , IL-6, IL-10, and tumor necrosis factor (TNF)-␣ ] ( 14 ). A large body of evidence suggests that limiting infl ammation and cytokine production by dietary n-3 PUFA (EPA and DHA) represents one of the potential mechanisms by which fi sh oil is atheroprotective ( 41,42 …”