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The role of cell death in atherosclerosis remains ill-defined, however, a growing body of evidence suggests that cell death stimulates atherogenesis through the induction of inflammation and enlargement of the necrotic core. Although there is solid evidence to suggest that lipid oxidation and toxicity are linked, indications that protein oxidation may play an important role in cytotoxicity are numerous. The abundance of dead cells in atherosclerotic plaques and their co-localization with HOCl-modified proteins provides an opening for the suggestion that the products of protein oxidation may be at the heart of oxLDL-induced cell death. Examination of the modification of LDL and albumin by HOCl, and the cytotoxicity of these oxidised molecules were the focus of this study, along with the elucidation of their cell death mechanisms toward U937 cells. Measurement of lipid peroxidation markers, TBARS and 7-ketocholesterol, showed no significant increase in HOCl-oxLDL compared to native levels although all α-tocopherol had been lost. In contrast there was a large loss of tyrosine, of which a small percentage went to dityrosine, indicating that the protein moiety of LDL was the main target of HOCl attack. Albumin became fragmented and smeared on SDS-PAGE gels with increasing HOCl/BSA molar ratios. In addition there was significant reduction in tyrosine levels and a small increase in dityrosine. Both HOCl-oxLDL and oxidised albumin (oxALB) caused concentration-dependent cell viability loss in U937 cells following a significant drop in intracellular GSH concentration, coinciding with a peak in oxidative stress. Removal of chloramines with methionine significantly reduced the toxicity of oxALB, but at higher concentrations this effect was reduced. This was in contrast to HOCl-oxLDL where the removal of chloramines had no effect on its toxicity. Morphological observations of cell swelling, cell membrane integrity loss and rupture, along with flow cytometry results indicate that U937 cells underwent necrosis, but only after intracellular GSH was lost. Intracellular GSH and cell viability loss were prevented by 200 μM extracellular 7,8-dihydroneopterin (78NP), indicating that 78NP scavenging of ROS generated in response to the oxidised proteins was sufficient to prevent cell death. This study demonstrates the cytotoxicity of HOCl-damaged LDL and albumin is likely due to a common oxidative product or structural motif which may be active within atherosclerotic plaques.

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Atherosclerosis is the primary underlying pathology of CVD. Dietary treatment may be considered as one of the initial steps in the prevention of atherosclerosis. Replacing refined carbohydrate source of a cholesterol- enriched diet with antioxidant rich whole grain and inclusion of phytonutrition in the diet such as wild rice and phytosterols may reduce cardiovascular risk factors. The wild rice (Zizania palustris L.), an annual plant native to aquatic areas of the northern America, receives much attention by researchers because of its potent nutritional and phytochemical contents. Furthermore, another dietary component with cardiovascular benefits is the inclusion of plant sterols in our daily diet. The aim of this study was to investigate the antiatherogenic activity of wild rice in combination with phytosterols in LDL-r-KO mice. Male LDL-r-KO mice were divided into 4 groups receiving one of the following experimental diets for 20 weeks: 1. Atherogenic diet, 2.Wild rice (as the main source of dietary carbohydrates) diet, 3. 2% Phytosterols-enriched diet and 4. Diet containing both wild rice and 2 % phytosterols. Blood samples were collected through jugular vein during study, and at sacrifice through cardiac puncture; the heart and fecal materials were collected and used for biochemical and histological examinations. The supplementation of wild rice in combination with phytosterols to an atherogenic diet for up to 20 weeks significantly reduced the total plasma concentrations of cholesterol (TC) in LDLr-KO mice. However, there was no significant difference in triglyceride (TG) in wild rice in combination with phytosterols after 20 week exposure of diet. Further, wild rice in combination with phytosterols resulted in increased fecal excretion of cholesterol. Also, there was reduction in the development of atherosclerotic lesion in the group of mice supplemented with wild rice in combination with 2% phytosterols (w/w). Our data support that combination of plant sterols and wild rice does not have additive effect in lowering cardiovascular risk.

Dietary flaxseed intake has exhibited both cardioprotective and anti-atherogenic properties. Regardless, it remains unclear whether these beneficial effects extent to the regression of atherosclerotic plaques or the resolution of cholesterol-induced vascular contractile dysfunction. In the present study, we intended to determine whether dietary flaxseed has the capacity to ameliorate vascular function abnormalities and induce atherosclerotic plaque regression. As results from previous studies using a nutritional intervention to induce atherosclerotic regression may have been confounded by premature initiation of the intervention, an appropriate feeding regimen was developed to adequately evaluate flaxseeds’ effects on atherosclerotic plaque regression. New Zealand white rabbits were utilized in two studies. To establish clear evidence of plaque growth stabilization, animals received 4 weeks of a 1% cholesterol-supplemented diet. An initial subset of animals was immediately examined. The remaining animals were fed regular rabbit chow and examined at intervals up to 28 weeks. To ascertain flaxseeds’ effects on atherosclerotic plaque regression and vascular contractile function, animals were randomly assigned to a control group fed a regular diet for 12 weeks (Group I) or an experimental group fed a 1% cholesterol-supplemented diet for 4 weeks followed by a regular diet for 8 weeks (Group II). The control and a subset of experimental animals were examined immediately afterwards. The remaining experimental animals were given an additional 8 or 14 weeks of either a regular diet (Group III and V, respectively) or a 10% flaxseed-supplemented diet (Group IV and VI, respectively) and were examined afterwards. Cholesterol feeding followed by 8 weeks of withdrawal from cholesterol not only resulted in the development and stabilization of atherosclerotic plaques but also impaired the maximum contraction caused by norepinephrine and the relaxation response to acetylcholine. An additional 14 weeks of regular diet reduced the amount of plaques on the aorta while flax-supplementation resulted in a further reduction in plaques. Nevertheless, both treatments were unable to achieve statistical significance. Flax- supplemented and regular diets improved vessel relaxation and contraction; however, negligible changes in the relaxation response induced by sodium nitroprusside were observed. Dietary flaxseed may accelerate the regression of atherosclerotic plaques. Moreover, the known beneficial effects of flaxseed do not extend to restoration of vascular function.

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