Dietary flaxseed has been shown to have potent antiatherogenic effects in rabbits. The purpose of the present study was to investigate the antiatherogenic capacity of flaxseed in an animal model that more closely represents the human atherosclerotic condition, the LDL receptor-deficient mouse (LDLrKO), and to identify the cellular mechanisms for these effects. LDLrKO mice were administered a regular diet (RG), a 10% flaxseed-supplemented diet (FX), or an atherogenic diet containing 2% cholesterol alone (CH) or supplemented with 10% flaxseed (CF), 5% flaxseed (CF5), 1% flaxseed (CF1), or 5% coconut oil (CS) for 24 wk. LDLrKO mice fed a cholesterol-supplemented diet exhibited a rise in plasma cholesterol without a change in triglycerides and an increase in atherosclerotic plaque formation. The CS mice exhibited elevated levels of plasma cholesterol, triglycerides, and saturated fatty acids and an increase in plaque development. Supplementation of the cholesterol-enriched diet with 10% (wt/wt) ground flaxseed lowered plasma cholesterol and saturated fatty acids, increased plasma ALA, and inhibited plaque formation in the aorta and aortic sinus compared with mice fed a diet supplemented with only dietary cholesterol. The expression of proliferating cell nuclear antigen (PCNA) and the inflammatory markers IL-6, mac-3, and VCAM-1 was increased in aortic tissue from CH and CS mice. This expression was significantly reduced or normalized when flaxseed was included in the diet. Our results demonstrate that dietary flaxseed can inhibit atherosclerosis in the LDLrKO mouse through a reduction of circulating cholesterol levels and, at a cellular level, via antiproliferative and anti-inflammatory actions.

-Dietary flaxseed has significant anti-atherogenic effects. However, the limits of this action and its effects on vascular contractile function are not known. We evaluated the effects of flaxseed supplementation on atherosclerosis and vascular function under prolonged hypercholesterolemic conditions in New Zealand White rabbits assigned to one of four groups for 6, 8, or 16 wk of feeding: regular diet (RG), 10% flaxseed-supplemented diet (FX), 0.5% cholesterol-supplemented diet (CH), and 0.5% cholesterol-and 10% flaxseed-supplemented diet (CF). Cholesterol feeding resulted in elevated plasma cholesterol levels and the development of atherosclerosis. The CF group had significantly less atherosclerotic lesions in the aorta and carotid arteries after 6 and 8 wk than the CH animals. However, the antiatherogenic effect of flaxseed supplementation was completely attenuated by 16 wk. Maximal tension induced in aortic rings either by KCl or norepinephrine was not impaired by dietary cholesterol until 16 wk. This functional impairment was not prevented by including flaxseed in the high-cholesterol diet. Aortic rings from the cholesterol-fed rabbits exhibited an impaired relaxation response to acetylcholine at all time points examined. Including flaxseed in the high-cholesterol diet completely normalized the relaxation response at 6 and 8 wk and partially restored it at 16 wk. No significant changes in the relaxation response induced by sodium nitroprusside were observed in any of the groups. In summary, dietary flaxseed is a valuable strategy to limit cholesterol-induced atherogenesis as well as abnormalities in endothelial-dependent vasorelaxation. However, these beneficial effects were attenuated during prolonged hypercholesterolemic conditions. linseed; acetylcholine; nutrition; polyunsaturated fatty acids; vascular relaxation ATHEROSCLEROSIS IS THE leading cause of cardiovascular morbidity and mortality in North America (77). Atherosclerosis induces two significant pathological processes: an ischemic event due to blood flow obstruction and vascular contractile dysfunction. It is well known that atherosclerosis is associated with elevated circulating cholesterol levels. Elevated plasma cholesterol concentrations induced by cholesterol feeding result in the development of atherosclerosis and an impairment in endothelium-dependent vasodilation in rabbits (9,26,29,30,36). The development of interventions to inhibit cholesterolinduced atherosclerosis and the associated vascular dysfunction have received much attention because of this strong association. For example, there is an increasing interest in nutritional interventions that may prevent the development of atherosclerosis and protect against the vascular function abnormalities induced by cholesterol consumption. Flaxseed is one such novel dietary intervention. Flaxseed is a good source of soluble and insoluble dietary fiber and is the richest plant source of ␣-linolenic acid [ALA; C18:3 n-3, omega-3 (n-3) fatty acid] as well as the lignan secoisolariciresinol digluco...

In summary, ingestion of flax oil and milled flaxseed delivered significant levels of ALA to the plasma whereas whole flaxseed did not. Whole seed and oil preparations induced adverse gastrointestinal effects within 4 weeks and these were severe enough to induce the withdrawal of some subjects from these two groups. No one withdrew from the group that ingested milled flaxseed and, therefore, may represent a good form of flaxseed to avoid serious side-effects and still provide significant increases in ALA to the body.

Background: Dietary flaxseed may have beneficial cardiovascular effects. An aged population has a higher incidence of cardiovascular disease, but they may react differently to flaxseed in the diet. Objective: To investigate the response, over a period of 4 weeks, of subjects aged 18-29 or 45-69 years to a diet containing the same amount of a-linolenic acid (ALA) (6 g) introduced in the form of ground flaxseed (30 g) or flaxseed oil. Results: All subjects who received flaxseed oil showed a significant increase in plasma ALA and eicosapentaenoic acid (EPA) concentrations over the course of this study. Subjects who received ground flaxseed in the 18-29-year-old group showed a statistically significant increase in their plasma ALA levels, and although there was a trend in the same direction for the 45-69-year-old subjects, this did not achieve statistical significance. The diets induced no major changes in platelet aggregation, plasma total cholesterol, low-density lipoprotein or high-density lipoprotein cholesterol levels in any of the groups. Younger subjects showed a decrease in triglyceride (TG) values compared with older subjects. There were no significant side effects that caused compliancy issues. Conclusion: Subject age does not seem to be a major determining factor in influencing ALA absorption from a flaxseedsupplemented diet nor in the metabolism of ALA to EPA in the groups fed flaxseed oil. Concerns about side effects in older subjects administered a higher fiber load in a flaxseed-supplemented diet are not justified. However, younger but not older subjects showed a beneficial decrease in circulating TGs due to flaxseed supplementation.

Hypercholesterolemia indirectly increases the risk for myocardial infarction by enhancing the ability of platelets to aggregate. Diets enriched with polyunsaturated fatty acids (PUFAs) have been shown to reduce the detrimental effects of cholesterol on platelet aggregation. This study investigated whether dietary hempseed, a rich source of PUFAs, inhibits platelet aggregation under normal and hypercholesterolemic conditions. Male New Zealand white rabbits were fed one of 6 dietary interventions: regular control diet (RG); control diet + 10% hempseed (HP); control diet + 10% partially delipidated hempseed (DHP); control diet + 0.5% cholesterol (OL); control diet + 0.5% cholesterol + 10% hempseed (OLHP); control diet + 5% coconut oil (CO). After 8 weeks, blood was collected to measure ADP- and collagen-induced platelet aggregation and plasma levels of fatty acids, cholesterol, and triglycerides. The hempseed-fed animals (HP and OLHP) displayed elevated plasma levels of PUFAs and a prominent enhancement in 18:3n-6 (gamma-linolenic acid, GLA) levels, a unique PUFA found in hempseed. The cholesterol-supplemented groups (OL and OLHP) had significantly elevated plasma levels of cholesterol and triglycerides, but platelet aggregation was significantly augmented only in the OL group. The addition of hempseed to this diet (OLHP) normalized aggregation. The direct addition of GLA to the OL platelet samples blocked the cholesterol-induced stimulation of platelet aggregation. The results of this study demonstrate that when hempseed is added to a cholesterol-enriched diet, cholesterol-induced platelet aggregation returns to control levels. This normalization is not due to a reduction in plasma cholesterol levels, but may be partly due to increased levels of plasma GLA.