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Abstract-Flaxseed contains ω-3 fatty acids, lignans, and fiber that together may provide benefits to patients with cardiovascular disease. Animal work identified that patients with peripheral artery disease may particularly benefit from dietary supplementation with flaxseed. Hypertension is commonly associated with peripheral artery disease. The purpose of the study was to examine the effects of daily ingestion of flaxseed on systolic (SBP) and diastolic blood pressure (DBP) in peripheral artery disease patients. In this prospective, double-blinded, placebo-controlled, randomized trial, patients (110 in total) ingested a variety of foods that contained 30 g of milled flaxseed or placebo each day over 6 months. Plasma levels of the ω-3 fatty acid α-linolenic acid and enterolignans increased 2-to 50-fold in the flaxseed-fed group but did not increase significantly in the placebo group. Patient body weights were not significantly different between the 2 groups at any time. SBP was ≈10 mm Hg lower, and DBP was ≈7 mm Hg lower in the flaxseed group compared with placebo after 6 months.

-Hyperhomocysteinemia is an independent risk factor for cardiovascular disorders. Elevated plasma homocysteine (Hcy) concentration is associated with other cardiovascular risk factors. We previously reported that Hcy stimulated cholesterol biosynthesis in HepG2 cells. In the present study, we investigated the underlying mechanisms of Hcy-induced hepatic cholesterol biosynthesis in an animal model. Hyperhomocysteinemia was induced in Sprague-Dawley rats by feeding a highmethionine diet for 4 wk. The mRNA expression and the enzyme activity of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase were significantly increased in livers of hyperhomocysteinemic rats. There were marked hepatic lipid accumulation and an elevation of plasma cholesterol concentration in hyperhomocysteinemic rats. Three transcription factors, namely, sterol regulatory element-binding protein-2 (SREBP-2), cAMP response element-binding protein (CREB), and nuclear factor Y (NF-Y) were activated in livers of hyperhomocysteinemic rats. Upon Hcy treatment of hepatocytes, there was a significant increase in HMG-CoA reductase mRNA expression in these cells. The activation of SREBP-2, CREB, and NF-Y preceded the increase in HMG-CoA reductase expression in Hcy-treated cells. Pretreatment of hepatocytes with inhibitors for transcription factors not only blocked the activation of SREBP-2, CREB, and NF-Y but also attenuated Hcy-induced HMG-CoA reductase mRNA expression. These results suggested that hyperhomocysteinemia-induced activation of SREBP-2, CREB, and NF-Y was responsible for increased cholesterol biosynthesis by transcriptionally regulating HMG-CoA reductase expression in the liver leading to hepatic lipid accumulation and subsequently hypercholesterolemia. In conclusion, the stimulatory effect of Hcy on hepatic cholesterol biosynthesis may represent an important mechanism for hepatic lipid accumulation and cardiovascular disorder associated with hyperhomocysteinemia.homocysteine; 3-hydroxy-3-methylglutaryl coenzyme A reductase; cAMP response element-binding protein; sterol regulatory elementbinding protein-2; nuclear factor Y HYPERHOMOCYSTEINEMIA, an elevation of blood homocysteine (Hcy) concentration, is considered an independent risk factor for cardiovascular and cerebrovascular disorders (7,37,48). The mechanisms responsible for hyperhomocysteinemia-associated cardiovascular disorders are still under investigation.

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.

H2O2 alters gene expression in many cell types. Alterations in nuclear import of transcription factors or similar key proteins may be responsible for these changes. To investigate this possibility, a cytosolic nuclear import cocktail was treated with varying [H2O2] and used in import assays. H2O2 caused a dose- and time-dependent inhibition of import at concentrations as low as 100 μM. Catalase reversed this effect. H2O2 treatment of permeablized cells did not affect import, suggesting that H2O2 was acting on a cytosolic factor. Treatment of import cocktail with two different free radical generating systems had no effect, but treatment of permeablized cells inhibited import, suggesting H2O2 works via a distinct process from hydroxyl or superoxide radicals. Pretreatment of import cocktail with genistein reversed the effect of H2O2 on import. Western blotting revealed that H2O2 activated ERK2. The specific MEK1/2 inhibitor, PD98059, completely blocked the effects of H2O2 on import. Activated ERK2 mimicked H2O2's effect on import. Immunocytochemistry revealed that H2O2 treatment of whole cells increased cytosolic Ran/TC4 levels, an effect reversible by catalase or PD98059. These data demonstrate that H2O2 inhibits nuclear protein import and that this effect is mediated by mitogen-activated protein (MAP) kinase activation, possibly by altering Ran/TC4 function.

Abstract-In a randomized, double-blinded, controlled clinical trial, participants with peripheral arterial disease (75% hypertensive) consumed 30 g of milled flaxseed/d for 6 months. The flaxseed group exhibited significant reductions in systolic (−10 mm Hg) and diastolic (−7 mm Hg) blood pressure. Flaxseed contains the n3 fatty acid α-linolenic acid. Plasma α-linolenic acid increased with ingestion of flaxseed and was inversely associated with blood pressure. However, the antihypertensive mechanism was unclear. Oxylipins derived from polyunsaturated fatty acids regulate vascular tone. Therefore, the objective was to examine whether flaxseed consumption altered plasma oxylipins in a manner that influenced blood pressure. Plasma of FlaxPAD (Flaxseed for Peripheral Arterial Disease) participants underwent solid phase extraction and high-performance liquid chromatography-mass spectrometry/mass spectrometry analysis. The flaxseed group exhibited significant decreases in 8 plasma oxylipins versus control. Six of these (5,6-, 8,9-, 11,12-, 14,15-dihydroxyeicosatrienoic acid and 9,10-and 12,13-dihydroxyoctadecenoic acid) were products of soluble epoxide hydrolase, a pharmacological target for antihypertensive treatment. Patients exhibiting a decrease in total plasma soluble epoxide hydrolase-derived oxylipins, exhibited a significant decrease in systolic blood pressure (mean [ and infarction size 23 in animal models. The proposed relationship between epoxygenase-derived oxylipins and hypertension is depicted in Figure 1.95%To test the hypothesis that flaxseed decreased the levels of oxylipins associated with inflammation and vasoconstriction, the study objectives were 3-fold: (1) to characterize and quantify the plasma oxylipin profile of participants with PAD, (2) to compare changes in plasma oxylipin concentrations in the control and flaxseed groups, and (3) to determine the mechanism whereby any changes in oxylipins may have influenced blood pressure in the FlaxPAD Trial. Methods Participants and Food ProductsA randomized, double-blinded, parallel, controlled clinical trial was established to determine the cardiovascular effects of dietary flaxseed in patients with PAD.24 Seventy-five percent of the participants were diagnosed as hypertensive at baseline (blood pressure ≥140/90 mm Hg).2,24 Participants (n=110) consumed food products containing either 30 g of milled flaxseed (treatment) or a combination of mixed dietary oils, milled wheat, and bran (control) for 6 months. Further details of the food product composition, 25,26 participant enrollment, intervention allocation, clinical characteristics, and blood pressure outcomes have been previously published.2,24 The trial is available at http://www.clinicaltrials.gov/ct2/show/NCT00781950?term=grant+p ierce+flax&rank=1.All participants provided informed consent, and all procedures were performed according to institutional guidelines. The trial was approved by Health Canada and its Natural Health Product Directorate, the University of Manitoba Research Ethics Board,...

-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...

SumtnaryIt is widely recognized that calcium is of singular importance in the viability of the myocardial cell, nonetheless little is known concerning the precise nature of the action of calcium in myocardium as to how it maintains the life of the cell and how it may dictate the death of the cell. However, recent advances in research involved with the study of calcium movement in the heart have been highly valuable for the formulation of new concepts with respect to the physiological and pathological aspects of calcium metabolism in the myocardium. It is becoming clear that calcium movements are closely related to cardiac eleetrophysiological events, contractile function, membrane integrity and energy metabolism. In particular, a novel theory involving phosphatidylinositol turnover and Ca2+-dependent ATPase activation has been advanced regarding the mechanism and control of calcium entry into the cardiac cell upon excitation. Alterations in the regulation of calcium metabolism through the interaction of a number of separate elements may affect calcium distribution in the cell and thereby may change cardiac function and metabolism. The part calcium plays in the genesis of pathological states in the myoeardium is discussed in the light of research employing various experimental protocols. Intracellular calcium overload and deficiency are postulated to contribute to cardiac contractile failure and cell death through a number of distinct mechanisms. It is now a real challenge to understand the precise nature of processes associated with the occurrence of intracellular calcium overload or intracellular calcium deficiency in order to achieve proper management of cardiac disorders.