Search

Background: Dietary flaxseed lowers cholesterol in healthy subjects with mild biomarkers of cardiovascular disease (CVD)., Objective: The aim was to investigate the effects of dietary flaxseed on plasma cholesterol in a patient population with clinically significant CVD and in those administered cholesterol-lowering medications (CLMs), primarily statins., Methods: This double-blind, randomized, placebo-controlled trial examined the effects of a diet supplemented for 12 mo with foods that contained either 30 g of milled flaxseed [milled flaxseed treatment (FX) group; n = 58] or 30 g of whole wheat [placebo (PL) group; n = 52] in a patient population with peripheral artery disease (PAD). Plasma lipids were measured at 0, 1, 6, and 12 mo., Results: Dietary flaxseed in PAD patients resulted in a 15% reduction in circulating LDL cholesterol as early as 1 mo into the trial (P = 0.05). The concentration in the FX group (2.1 ± 0.10 mmol/L) tended to be less than in the PL group (2.5 ± 0.2 mmol/L) at 6 mo (P = 0.12), but not at 12 mo (P = 0.33). Total cholesterol also tended to be lower in the FX group than in the PL group at 1 mo (11%, P = 0.05) and 6 mo (11%, P = 0.07), but not at 12 mo (P = 0.24). In a subgroup of patients taking flaxseed and CLM (n = 36), LDL-cholesterol concentrations were lowered by 8.5% ± 3.0% compared with baseline after 12 mo. This differed from the PL + CLM subgroup (n = 26), which increased by 3.0% ± 4.4% (P = 0.030) to a final concentration of 2.2 ± 0.1 mmol/L., Conclusions: Milled flaxseed lowers total and LDL cholesterol in patients with PAD and has additional LDL-cholesterol-lowering capabilities when used in conjunction with CLMs. This trial was registered at clinicaltrials.gov as NCT00781950., (© 2015 American Society for Nutrition.)

Cardiovascular disease remains the leading cause of death today. Trans fatty acids have been identified as an important cause of cardiovascular disease and the resulting clinical end points such as strokes and heart attacks. Although legislative efforts have limited the trans fats in our diet, significant amounts remain. Understanding the impact trans fats have on our body, therefore, remains a critical focus of study. In addition, paradoxically, recent research has now identified an important cardioprotective role for a sub-category of trans fats, the ruminant trans fats. Learning more about the mechanisms responsible for not only the toxic actions of trans fats but also their potential as beneficial compounds within our diet is essential to modulate cardiovascular disease today., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Heat shock proteins play important housekeeping roles in a variety of cells within the body during normal control conditions. The many different functions for heat shock proteins in the cell depend upon the specific heat shock protein involved. Each protein is nominally differentiated based upon its molecular size. However, in addition to their role in normal cell function, heat shock proteins may play an even more important role as pro-survival proteins conserved through evolution to protect the cell from a variety of stresses. The ability of a cell to withstand these environmental stresses is critical to its capacity to adapt and remain viable. Loss of this ability may lead to pathological states. Abnormal localization, structure or function of the heat shock proteins has been associated with many pathologies, including those involving heart disease. Heat shock proteins like HSP60 and HSP70 in particular have been identified as playing important roles in inflammation and immune reactions. Inflammation has been identified recently as an important pathological risk factor for heart disease. It is perhaps not surprising therefore, that heat shock protein family has been increasingly identified as an important intracellular pathway associated with inflammatory-mediated heart conditions including atherosclerosis. This paper reviews the evidence in support of a role for heat shock proteins in cardiovascular disease and the potential to target these proteins to alter the progression of atherosclerotic disease.

Aims: During cardiac hypertrophy, cardiomyocytes (CMs) increase in the size and expression of cytoskeletal proteins while reactivating a foetal gene programme. The process is proposed to be dependent on increased nuclear export and, since nuclear pore trafficking has limited capacity, a linked decrease in import. Our objective was to investigate the role of nuclear import and export in control of hypertrophy in rat and human heart failure (HF)., Methods and Results: In myocardial tissue and isolated CMs from patients with dilated cardiomyopathy, nuclear size was increased; Nucleoporin p62, cytoplasmic RanBP1, and nuclear translocation of importins (α and β) were decreased while Exportin-1 was increased. CM from a rat HF model 16 weeks after myocardial infarction (MI) reproduced these nuclear changes. Nuclear import, determined by the rate of uptake of nuclear localization sequence (NLS)-tagged fluorescent substrate, was also decreased and this change was observed from 4 weeks after MI, before HF has developed. Treatment of isolated rat CMs with phenylephrine (PE) for 48 h produced similar cell and nuclear size increases, nuclear import and export protein rearrangement, and NLS substrate uptake decrease through p38 MAPK and HDAC-dependent pathways. The change in NLS substrate uptake occurred within 15 min of PE exposure. Inhibition of nuclear export with leptomycin B reversed established nuclear changes in PE-treated rat CMs and decreased NLS substrate uptake and cell/nuclear size in human CMs., Conclusions: Nuclear transport changes related to increased export and decreased import are an early event in hypertrophic development. Hypertrophy can be prevented, or even reversed, by targeting import/export, which may open new therapeutic opportunities., (© The Author 2014. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Hypertension is the single largest risk factor attributed to mortality in the world. Medications are the primary treatment for hypertension; however, adherence to drug regimens is low (~50 %). Low adherence may be a contributing factor leading to uncontrolled blood pressure in patients. An effective alternative or complement to medications in managing hypertension is through lifestyle modifications. Adopting a healthy diet is a valuable strategy. A recent, randomized controlled year-long trial observed impressive reductions in blood pressure in patients with hypertension consuming flaxseed daily. Therefore, attention has been garnered for flaxseed as a potentially valuable strategy for the management of hypertension. This review will highlight the recent data for flaxseed and its extracts in blood pressure regulation in both animal models and clinical trials. Insight into the proposed anti-hypertensive mechanism of flaxseed and the implications of flaxseed as a potential global anti-hypertensive therapy will be discussed.

Background and Aims: Oxylipins, including eicosanoids, are highly bioactive molecules endogenously produced from polyunsaturated fatty acids. Oxylipins play a key role in chronic disease progression. It is possible, but unknown, if oxylipin concentrations change with the consumption of functional foods or differ with subject age., Methods: Therefore, in a parallel comparator trial, 20 healthy individuals were recruited into a younger (19-28years) or older (45-64years) age group (n=10/group). Participants ingested one muffin/day containing 30g of milled flaxseed (6g alpha-linolenic acid) for 4weeks. Plasma oxylipins were isolated through solid phase extraction, analyzed with HPLC-MS/MS targeted lipidomics, and quantified with the stable isotope dilution method., Results: At baseline, the older group exhibited 13 oxylipins ≥2-fold the concentration of the younger group. Specifically, pro-inflammatory oxylipins 5-hydroxyeicosatetraenoic acid, 9,10,13-trihydroxyoctadecenoic acid, and 9,12,13-trihydroxyoctadecenoic acid were significantly greater in the older (1.1±0.23nM, 5.6±0.84nM, and 4.5±0.58nM, respectively) versus the younger group (0.34±0.12nM, 3.5±0.33nM, and 3.0±0.24nM, respectively) (p<0.05). After 4weeks of flaxseed consumption the number of oxylipins that were ≥2-fold higher in the older versus the younger group was reduced to 3. 5-Hydroxyeicosatetraenoic acid, 9,10,13-trihydroxyoctadecenoic acid, and 9,12,13-trihydroxyoctadecenoic acid decreased in the older group to concentrations equivalent to the younger group after flaxseed consumption., Conclusion: These data suggest a potential role for oxylipins in the aging process and how nutritional interventions like flaxseed can beneficially disrupt these biological changes associated with inflammation and aging., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Unlabelled: 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 [95% confidence interval], -7.97 [-14.4 to -1.50] mm Hg) versus those who exhibited increased plasma soluble epoxide hydrolase-derived oxylipins (+3.17 [-4.78 to 11.13] mm Hg). These data suggest that a flaxseed bioactive may have decreased blood pressure via soluble epoxide hydrolase inhibition. Using a soluble epoxide hydrolase inhibitor screening assay, increasing concentrations of α-linolenic acid decreased soluble epoxide hydrolase activity (P=0.0048; ρ=-0.94). In conclusion, α-linolenic acid in flaxseed may have inhibited soluble epoxide hydrolase, which altered oxylipin concentrations that contributed to the antihypertensive effects in patients with peripheral arterial disease., Clinical Trial Registration Url: http://www.clinicaltrials.gov. Unique identifier: NCT00781950., (© 2014 American Heart Association, Inc.)

Background: In 2013 the World Health Organization deemed hypertension as a global crisis as it is the leading risk factor attributed to global mortality. Therefore, there is a great need for effective alternative treatment strategies to combat a condition that affects 40% of adults worldwide. Recently, the FlaxPAD Trial observed a significant reduction in systolic and diastolic blood pressure in hypertensive patients with peripheral arterial disease that consumed 30 g of milled flaxseed per day for one year. However, these patients were already on anti-hypertensive medication. Therefore, there is a need to assess if dietary flaxseed can effectively reduce blood pressure in the absence of peripheral arterial disease and anti-hypertensive medication in newly diagnosed hypertensive patients., Methods/design: The HYPERFlax Trial is a parallel, superiority, phase II/III, randomized, double-blinded, controlled clinical trial. St. Boniface Hospital and the Health Sciences Centre of Winnipeg, Canada, will recruit 100 participants newly diagnosed with stage 1 hypertension who have yet to be administered anti-hypertensive medication. Participants will be randomly allocated with a 1:1 ratio into a flaxseed or control group and provided food products to consume daily for six months. At baseline, two, four, and six months, participant assessments will include the primary outcome measure, averaged automated blood pressure, and secondary measures: 24-hour food recall, international physical activity questionnaire, anthropometrics, and blood and urine sampling for biochemical analysis. Plasma will be assessed for lipids, metabolomics profiling, and molecules that regulate vascular tone. Urine will be collected for metabolomics profiling. With an estimated dropout rate of 20%, the trial will have a power of 0.80 to detect differences between groups and across time, out of an effect size of 0.7 (SD) at an α level of 0.05., Discussion: This trial will determine if dietary flaxseed is efficacious over six months as an anti-hypertensive therapy in subjects newly diagnosed with hypertension. If flaxseed can effectively reduce blood pressure as a monotherapy, then flaxseed will provide individuals on a global basis with a cost-effective food-based strategy to control hypertension., Trial Registration: NCT01952340, Registered 24 September 2013.

It is now well known that a cardiomyopathic state accompanies diabetes mellitus. Although insulin injections and conventional hypoglycemic drug therapy have been of invaluable help in reducing cardiac damage and dysfunction in diabetes, cardiac failure continues to be a common cause of death in the diabetic population. The use of alternative medicine to maintain health and treat a variety of diseases has achieved increasing popularity in recent years. The goal of alternative therapies in diabetic patients has been to lower circulating blood glucose levels and thereby treat diabetic complications. This paper will focus its discussion on the role of vanadium on diabetes and the associated cardiac dysfunction. Careful administration of a variety of forms of vanadium has produced impressive long-lasting control of blood glucose levels in both Type 1 and Type 2 diabetes in animals. This has been accompanied by, in many cases, a complete correction of the diabetic cardiomyopathy. The oral delivery of vanadium as a vanadate salt in the presence of tea has produced particularly impressive hypoglycemic effects and a restoration of cardiac function. This intriguing approach to the treatment of diabetes and its complications, however, deserves further intense investigation prior to its use as a conventional therapy for diabetic complications due to the unknown long-term effects of vanadium accumulation in the heart and other organs of the body.

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. Patients who entered the trial with a SBP ≥ 140 mm Hg at baseline obtained a significant reduction of 15 mm Hg in SBP and 7 mm Hg in DBP from flaxseed ingestion. The antihypertensive effect was achieved selectively in hypertensive patients. Circulating α-linolenic acid levels correlated with SBP and DBP, and lignan levels correlated with changes in DBP. In summary, flaxseed induced one of the most potent antihypertensive effects achieved by a dietary intervention.

Dietary flaxseed can retard the progression of atherosclerotic plaques. However, it remains unclear whether these antiatherogenic effects extend to plaque regression. In the present study, the therapeutic potential of dietary flaxseed on atherosclerotic plaque regression and vascular contractile function was evaluated using a novel rabbit model. Rabbits were randomly assigned to receive either a regular diet for 12 wk (group I) or a 1% cholesterol-supplemented diet for 4 wk followed by a regular diet for 8 wk (group II). The remaining experimental animals were treated as in group II but were fed for an additional 14 wk with either a regular diet (group III) or a 10% flaxseed-supplemented diet (group IV). Animals in group II showed clear evidence of plaque growth stabilization. Their vessels also exhibited significantly lower norepinephrine-induced contraction and an impaired relaxation response to acetylcholine compared with animals in group I. Dietary flaxseed supplementation resulted in a significant ≈40% reduction in plaque formation (P = 0.033). Animals in both groups II and III displayed improved contraction and endothelium-dependent vessel relaxation. Dietary flaxseed is a valuable strategy to accelerate the regression of atherosclerotic plaques; however, flaxseed intervention did not demonstrate a clear beneficial effect on the vessel contractile response and endothelium-dependent vasorelaxation.

Fatty acids have an important role in providing energy for sustained contractile activity and viability of the heart. However, considerable evidence now supports a role for fatty acids in the modulation of cardiovascular pathology as well. This may be beneficial or detrimental due to the structural differences in the various fatty acids. Polyunsaturated fatty acids appear to provide important protection to the heart during ischemic reperfusion challenge. Conversely, trans fatty acids are thought to mediate detrimental cardiac effects. Potentially pathological features of ischemic cardiomyocytes may be manifested as qualitative findings in studies of myocardial infarction and atherosclerosis. These general conclusions, however, are complicated by opposing effects that different fatty acids have even within the same group (i.e. n-6 versus n-3 fatty acids within the polyunsaturated fatty acids group, and industrial versus ruminant trans fats). Understanding more about how these fatty acid species alter ischemic myocardial injury is an increasingly attractive area of research. The identification of further targets of fatty acid interactions has great potential to provide valuable information for the modulation of cardiovascular disease.

Dietary interventions involving foods that are enriched in lignans, such as flaxseed, are drawing attention due to their beneficial protective effects in various diseases and human conditions. Accurate quantitation of key lignan metabolites such as enterodiol (END) and enterolactone (ENL) is necessary in order to identify factors that may influence overall bioavailability. Here we describe the validation of a novel supported liquid extraction (SLE) method for isolation of plasma enterolignans, END and ENL, using (2)H(6)-labeled isotopes with gas chromatography-mass spectrometry in micro selected ion storage (GC/MS-μSIS) mode. Following enzymatic hydrolysis and SLE extraction with 70:30 diethyl ether:ethyl acetate, enterolignans were rapidly separated within 8min. SLE in combination with GC/MS-μSIS gave high recoveries of 96.4% and 96.0% for END and ENL. Intra-assay precision ranged from 2.5 to 5.9% for both compounds whereas the inter-assay precision was 2.6-6.9%. SLE was also directly compared to liquid liquid extraction (LLE). Both techniques offered high precision and accuracy, however, SLE consistently enabled successful analyte extractions and derivatizations, unlike LLE, which had an ∼4% failure rate. SLE was also tested in a study where dietary milled flaxseed supplementation (30g/day for 1month) and enterolignan bioavailability was examined in a healthy, human population (n=10). Plasma total enterolignan levels significantly increased (P=0.002) at 4weeks relative to baseline. Average concentrations for END and ENL were 209nM and 304nM, respectively., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Mechanical stress contributes to hypertension and atherosclerosis partly through the stimulation of vascular smooth muscle cell (VSMC) proliferation. Oxidized low density lipoprotein (oxLDL) is another important atherogenic factor that can increase VSMC proliferation. The purpose of this study was to investigate whether oxLDL could further enhance the proliferative action of mechanical stretch on VSMC, and to determine the mechanism responsible for this interaction. Because nuclear protein import is critical in regulating gene expression, transcription, and cell proliferation, its involvement in the mitogenic effects of oxLDL and mechanical stress was studied. OxLDL enhanced the proliferative effects of mechanical stretch on its own in rabbit aortic VSMC, and induced increases in the expression of HSP60 in an additive manner. Adenoviral-mediated overexpression of HSP60 induced increases in cell proliferation compared with uninfected VSMC. Mechanical stretch and oxLDL stimulated the rate of nuclear protein import in VSMC and increased the expression of nucleoporins. These effects were sensitive to inhibition of the MAPK pathway. We conclude that oxLDL and mechanical stretch have a synergistic effect on VSMC proliferation. This synergistic effect is induced through a stimulation of nuclear protein import via HSP60 and an activation of the MAPK pathway.

Trans fats are not a homogeneous group of molecules and less is known about the cellular effects of individual members of the group. Vaccenic acid (VA) and elaidic acid (EA) are the predominant trans monoenes in ruminant fats and vegetable oil, respectively. Here, we investigated the mechanism of cell death induced by VA and EA on primary rat ventricular myofibroblasts (rVF). The MTT assay demonstrated that both VA and EA (200μM, 0-72 h) reduced cell viability in rVF (P<0.001). The FACS assay confirmed that both VA and EA induced apoptosis in rVF, and this was concomitant with elevation in cleaved caspase-9, -3 and -7, but not caspase-8. VA and EA decreased the expression ratio of Bcl2:Bax, induced Bax translocation to mitochondria and decrease in mitochondrial membrane potential (Δψ). BAX and BAX/BAK silencing in mouse embryonic fibroblasts (MEF) inhibited VA and EA-induced cell death compared to the corresponding wild type cells. Transmission electron microscopy revealed that VA and EA also induced macroautophagosome formation in rVF, and immunoblot analysis confirmed the induction of several autophagy markers: LC3-β lipidation, Atg5-12 accumulation, and increased beclin-1. Finally, deletion of autophagy genes, ATG3 and ATG5 significantly inhibited VA and EA-induced cell death (P<0.001). Our findings show for the first time that trans fat acid (TFA) induces simultaneous apoptosis and autophagy in rVF. Furthermore, TFA-induced autophagy is required for this pro-apoptotic effect. Further studies to address the effect of TFA on the heart may reveal significant translational value for prevention of TFA-linked heart disease., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Coronary heart disease is becoming a worldwide epidemic and diet and lifestyle are well known contributing factors. Identifying the kinds of foods that may have a cardioprotective or cardiotoxic effect and understanding their molecular mechanisms of action has become of increasing importance. Through largely epidemiological evidence, trans fatty acid (TFA) intake has been associated with a variety of cardiovascular complications including atherosclerosis. Traditionally, industrial TFAs (iTFAs) have been associated with these deleterious cardiovascular effects. However, there is a current body of research that suggests that ruminant trans fats (rTFAs) may have a cardioprotective role within the heart. The molecular mechanisms whereby TFAs are delivering their effects are largely unknown. In the following review, we discuss recent in vitro, animal and epidemiological research to better understand the effect of TFAs in the diet on cardiovascular disease, particularly atherosclerosis., (© 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Vanadium can induce potent hypoglycemic effects in type 1 and type 2 diabetes mellitus animals, but toxic adverse effects have inhibited the translation of these findings. Administration of vanadate in a black tea decoction has shown impressive hypoglycemic effects without evidence of toxicity in short-term studies. The purpose of this study was to investigate the hypoglycemic action and the toxic adverse effects of a tea/vanadate (T/V) decoction in diabetic rats over a 14-month treatment period. Streptozotocin-induced type 1 diabetes mellitus rats were orally gavaged with 40 mg sodium vanadate in a black tea decoction only when blood glucose levels were greater than 10 mmol/L. Glycemic status and liver and kidney function were monitored over 14 months. All of the diabetic rats in this treatment group (n = 25) required treatment with the T/V decoction at the start of the study to reduce blood glucose levels to less than 10 mmol/L. Diarrhea was uncommon among the T/V-treated animals during the first week of T/V treatment and was absent thereafter. There was no evidence of liver or kidney dysfunction or injury. From 2 to 6 months, fewer animals required the T/V treatment to maintain their blood glucose levels. After 9 months of treatment, none of the diabetic animals required any T/V to maintain their blood glucose levels at less than 10 mmol/L. Oral administration of a T/V decoction provides safe, long-acting hypoglycemic effects in type 1 diabetes mellitus rats. The typical glycemic signs of diabetes were absent for the last 5 months of the study., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Chlamydophila pneumoniae infection has been associated in previous studies with coronary artery disease. The live bacterium has been detected within atherosclerotic plaques and can induce the structural remodeling of the vessel wall. However, the direct effects of infection on the contractile characteristics of the arteries remain unknown. Left anterior descending coronary arteries isolated from porcine hearts were dissected and placed in culture medium for 72 hours before infection with C. pneumoniae. Contractile responses to high molar KCl and u46619 levels and relaxation responses to bradykinin and sodium nitroprusside were assessed at days 5 and 10 postinfection. C. pneumoniae induced decreases in both KCl- and u46619-induced contractile responses at both time points. The altered contractile responses coincided with a down-regulation of L-type Ca(2+) channels at both time points and inositol 1,4,5-triphosphate receptor (IP3R) levels at day 10 postinfection. Infection also induced attenuation of the endothelial-dependent relaxation response to bradykinin at day 10 postinfection. A decrease in endothelial nitric oxide synthase expression levels was noted at day 10 postinfection. Furthermore, an increase in superoxide production combined with an increase in p22phox expression levels was also observed at this time point. These findings indicate that C. pneumoniae infection can directly alter the vascular contractile responses in porcine coronary arteries, providing additional evidence for the role of C. pneumoniae infection in cardiovascular disease., (Copyright © 2012 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

An important part of training the next generation of physicians is ensuring that they are exposed to the integral role that research plays in improving medical treatment. However, medical students often do not have sufficient time to be trained to carry out any projects in biomedical and clinical research. Many medical students also fail to understand and grasp translational research as an important concept today. In addition, since medical training is often an international affair whereby a medical student/resident/fellow will likely train in many different countries during his/her early training years, it is important to provide a learning environment whereby a young medical student experiences the unique challenges and value of an international educational experience. This article describes a program that bridges the gap between the basic and clinical research concepts in a unique international educational experience. After completing two semester curricula at Alfaisal University in Riyadh, Kingdom of Saudi Arabia, six medical students undertook a summer program at St. Boniface Hospital Research Centre, in Winnipeg, MB, Canada. The program lasted for 2 mo and addressed advanced training in basic science research topics in medicine such as cell isolation, functional assessment, and molecular techniques of analysis and manipulation as well as sessions on the conduct of clinical research trials, ethics, and intellectual property management. Programs such as these are essential to provide a base from which medical students can decide if research is an attractive career choice for them during their clinical practice in subsequent years. An innovative international summer research course for medical students is necessary to cater to the needs of the medical students in the 21st century.

Unlabelled: Bakery products containing flaxseed, a rich source of alpha linolenic acid (ALA), may provide health benefits. However, the effect of adding flaxseed, especially in the high amounts required for use as the food supplement in clinical trials (23% by weight of the raw ingredients), may affect the flavor characteristics and consumer acceptability. Sensory attributes of bagels containing 30 g of milled flaxseed were evaluated by a 9 member trained panel using a descriptive test and by 89 participants using a consumer test. Grain/flax aroma and flavor were significantly higher for the flax bagels compared to the nonflax bagels. The cinnamon raisin bagel had significantly lower grain/flax aroma and flavor and significantly higher sweet aroma and taste compared to the plain and sunflower sesame types. Older consumers rated the appearance, color, and flavor of the bagels significantly higher than the younger consumers possibly leading to higher compliance in clinical studies for this age group. Bagels with flax showed a significantly lower mean value for flavor acceptability, overall acceptability, and frequency of eating compared to bagels without flax. Appearance, color, and texture acceptability showed no significant differences. The cinnamon raisin bagel had significantly higher flavor acceptance compared to sunflower sesame and plain bagels. In conclusion, for bagels containing 6 g ALA in the form of milled flaxseed, cinnamon raisin appears to be a promising flavoring alternative for ALA fortification for use in clinical trials or as part of the daily diet., Practical Application: Consumers are seeking functional foods that contain omega-3 fatty acids. Bagels made with 23% milled flaxseed (approximately 2 times the amount in regular flax baked products) provided 6 g ALA, an amount high enough to test the efficacy of ALA in human subjects without causing gastrointestinal distress. This study showed that flaxseed aroma and flavor were detected in fortified compared to nonfortified bagels but bagels with this high flaxseed amount were still acceptable with the addition of cinnamon raisin flavoring. Commercial bakeries can use these results to formulate healthy, tasty, and convenient products., (© 2011 Institute of Food Technologists®)

Aims: The atherogenic actions of Chlamydia pneumoniae (C. pneumoniae), a common respiratory pathogen, are dependent upon a high-cholesterol environment in vivo. It is possible that oxidized low-density lipoprotein (oxLDL) is responsible for promoting the atherogenic effects of C. pneumoniae through a stimulation of cell proliferation. This study determined whether oxLDL can enhance the mitogenic action of C. pneumoniae in vascular smooth muscle cells (VSMCs) and the involvement of mitogen-activated protein kinase (MAPK) pathways and heat shock protein 60 (HSP60) in these mechanisms., Methods and Results: Primary rabbit VSMCs were treated with live C. pneumoniae, heat-inactivated C. pneumoniae or infection medium, and subsequently incubated for up to 48 h in the presence or absence of oxLDL. Chlamydia pneumoniae infection alone stimulated cell proliferation and the addition of oxLDL significantly amplified this proliferative effect. This proliferation was accompanied by extracellular signal-regulated kinase-1 and -2 (ERK1/2) activation and an up-regulation of HSP60 expression. Changes in proliferation and HSP60 expression were attenuated by the inhibition of ERK1/2., Conclusion: These results indicate a novel role for oxLDL in promoting the mitogenic actions of C. pneumoniae in the vasculature. ERK1/2 is an important factor in the stress-mediated response and HSP60 up-regulation in VSMC. These data provide mechanistic evidence that C. pneumoniae may stimulate atherogenesis.

Dietary intake of industrially hydrogenated trans fatty acids (TFA) has been associated with coronary heart disease. Dietary flaxseed can inhibit atherosclerosis induced by dietary cholesterol. The aim of this study was to determine whether supplementing the diet with flaxseed could protect against atherosclerosis induced by a diet enriched in TFA. Low-density lipoprotein receptor-deficient (LDLr(-/-)) mice were fed 1 of 14 experimental diets for 14 wk containing one of two fat sources [regular (pork/soy) or trans fat] at two concentrations (4 or 8%) and supplemented with or without dietary cholesterol (2%), whole ground flaxseed, or one of the components of flaxseed [α-linolenic acid (ALA), defatted fiber, or lignan]. Adding flaxseed to the diet partially mitigated the rise in circulating cholesterol levels induced by the cholesterol-enriched diet. Atherosclerosis was stimulated by TFA and/or cholesterol. Including milled flaxseed to an atherogenic diet significantly reduced atherosclerosis compared with the groups that consumed cholesterol and/or TFA. ALA was the only component within flaxseed that could inhibit the atherogenic action of cholesterol and/or TFA on its own. Dietary flaxseed protects against atherosclerotic development induced by TFA and cholesterol feeding through its content of ALA.

Dietary flaxseed has cardioprotective effects that may be achieved through its rich content of the omega-3 fatty acid, alpha linolenic acid (ALA). Because ALA can be stored in adipose tissue, it is possible that some of its beneficial actions may be due to effects it has on the adipose tissue. We investigated the effects of dietary flaxseed both with and without an atherogenic cholesterol-enriched diet to determine the effects of dietary flaxseed on the expression of the adipose cytokines leptin and adiponectin. Rabbits were fed one of four diets: a regular (RG) diet, or a regular diet with added 0.5% cholesterol (CH), or 10% ground flaxseed (FX), or both (CF) for 8 weeks. Levels of leptin and adiponectin expression were assessed by RT-PCR in visceral adipose tissue. Consumption of flaxseed significantly increased plasma and adipose levels of ALA. Leptin protein and mRNA expression were lower in CH animals and were elevated in CF animals. Changes in leptin expression were strongly and positively correlated with adipose ALA levels and inversely correlated with levels of en face atherosclerosis. Adiponectin expression was not significantly affected by any of the dietary interventions. Our data demonstrate that the type of fat in the diet as well as its caloric content can specifically influence leptin expression. The findings support the hypothesis that the beneficial cardiovascular effects associated with flaxseed consumption may be related to a change in leptin expression.

Background: Flaxseed is an important source of alpha-linolenic acid an essential omega-3 fatty acid. The possibility that a supplementation of the diet with foods rich in alpha-linolenic acid, antioxidants and fiber (like flaxseed) has not been investigated., Methods/design: The primary objective is to determine whether consumption of a diet rich in FLAXseed over a one year period has any beneficial cardiovascular effects in patients with Peripheral Arterial Disease (FLAX-PAD study). This is a single center, prospective, double blinded, randomized controlled clinical trial aimed at in 110 patients over 40 years old and with peripheral arterial disease. Patients will receive 30 g of milled flaxseed (or placebo) per day. Primary endpoints are incidence of myocardial infarction and stroke. Secondary measures include: requirement for surgical interventions, exercise and cardiopulmonary performance, cardiac arrhythmias, serum lipid profile, arterial sufficiency, blood pressure, inflammatory profile, platelet function, changes in drug dosage levels, as well as nutrigenomic and biomarker profiles in the blood. Recruitment and baseline examinations started in October 2008. Baseline data of the 110 patients is shown., Conclusions: FLAX-PAD will generate data on the safety, tolerability, cardiovascular efficacy and genomic response to a diet rich in flaxseed. It will determine the effects on primary and secondary events (stroke, myocardial infarctions, angina pectoris, cardiac arrhythmias) as well as in secondary endpoints (exercise performance, blood pressure and circulating lipid levels) in patients with PAD., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Atherosclerosis was originally considered to be an ongoing process that was inevitably associated with age. However, plaques are highly dynamic, and are able to progress, stabilize or regress depending on their surrounding milieu. A great deal of research attention has been focused on understanding the involvement of high-density lipoprotein in atherosclerotic plaque regression. However, atherosclerotic plaque regression encompasses a variety of processes that can be grouped into three main areas: removal of lipids and necrotic material; restoration of endothelial function and repair of denuded areas; and cessation of vascular smooth muscle cell proliferation and phenotype reversal. In addition to the role of high-density lipoproteins in lipid removal, resident macrophages and foam cells are able to regain motility and rapidly migrate on milieu improvement, moving both lipids and necrotic material to regional lymph nodes. Neighbouring endothelial cells can proliferate and replace dead and dysfunctional cells. Circulating endothelial progenitor cells can similarly restore vessel function. Finally, abrogation of smooth muscle cell proliferation occurs secondarily to these processes. This information is integrated in the current article to present a comprehensive and clear depiction of plaque regression. This integrated view of regression is essential to optimize the pharmaceutical targeting of the many processes and pathways involved in plaque regression.

Unlabelled: Hempseed contains a unique combination of both omega-3 and omega-6 polyunsaturated fatty acids. In other studies, supplementation of the diet with selected polyunsaturated fatty acids has induced significant, beneficial cardiovascular effects. The purpose of the present study is to determine if hempseed ingestion over an 8-week period may provide protection to rabbits against the deleterious effects associated with dietary cholesterol supplementation., Methods: Male albino New Zealand White rabbits were randomly divided into one of six groups: the control diet (RG), the control diet then supplemented with (wt/wt) 5% coconut oil (CO), or 10% hempseed (HP), or 0.5% cholesterol (OL), or with both 10% hempseed and 0.5% cholesterol (OLHP) or with 10% hempseed that was partially delipidated (SC). Each day the rabbits were fed 125 grams of the appropriate diet over an 8-week period. Fatty acid analysis of tissue and diets was determined using gas chromatography. Vascular function testing of aortic rings was done in order to assess the response of the tissue to both contraction and relaxation stimuli. Aortic atherosclerotic plaque was quantified., Results: Cholesterol supplementation to the diet induced significant aortic plaque development. Dietary hempseed did not generate protection. The aorta obtained from rabbits fed the cholesterol-supplemented chow also exhibited defects in their contractile responses to KCl and norepinephrine and in relaxation to sodium nitroprusside (SNP).The addition of hempseed to this diet did not generate any improvement in contractile responses but had a modest protective effect on the cholesterol-induced defects in SNP-induced relaxation., Conclusions: Our data demonstrate that dietary hempseed provides mildly beneficial effects against contractile dysfunction associated with atherosclerotic vessels in the cholesterol-fed rabbit.

The human ether-à-go-go-related gene (hERG) encodes the pore-forming subunit of the rapidly activating delayed rectifier K(+) current (I(Kr)) important for cardiac repolarization. Dysfunction of the hERG channel causes long QT syndrome (LQTS). Although diverse compounds reduce the hERG current (I(hERG)) by blocking the channel, probucol, a cholesterol-lowering drug that causes LQTS, reduces I(hERG) by decreasing plasma-membrane hERG protein expression. Here, we investigated the mechanisms of probucol effects on hERG expression levels. Our data demonstrate that probucol accelerated the degradation of mature hERG channels, which associated with caveolin-1 (Cav1) in hERG-expressing HEK cells. In human embryonic kidney (HEK) cells without hERG expression, probucol promoted endogenous Cav1 degradation. In hERG-expressing HEK cells, overexpression of Cav1 enhanced, whereas knockdown of Cav1 impeded, probucol-induced reduction of mature hERG channels. Thus, probucol reduces hERG expression through accelerating Cav1 turnover. The effects of probucol on Cav1 and hERG result from probucol's cholesterol-disrupting action, because low-density lipoprotein (LDL), a potent cholesterol carrier, effectively prevented probucol-induced reduction of I(hERG) in hERG-expressing HEK cells and of I(Kr) in neonatal rat cardiomyocytes. Our data provide evidence that targeting hERG-interacting protein caveolin represents a novel mechanism for drugs to decrease hERG expression and cause LQTS.

Mitogen activated protein (MAP) kinases control eukaryotic proliferation, and import of kinases into the nucleus through the nuclear pore complex (NPC) can influence gene expression to affect cellular growth, cell viability and homeostatic function. The NPC is a critical regulatory checkpoint for nucleocytoplasmic traffic that regulates gene expression and cell growth, and MAP kinases may be physically associated with the NPC to modulate transport. In the present study, highly enriched NPC fractions were isolated and investigated for associated kinases and/or activity. Endogenous kinase activity was identified within the NPC fraction, which phosphorylated a 30 kD nuclear pore protein. Phosphomodification of this nucleoporin, here termed Nup30, was inhibited by apigenin and PD-98059, two MAP kinase antagonists as well as with SB-202190, a pharmacological blocker of p38. Furthermore, high throughput profiling of enriched NPCs revealed constitutive presence of all members of the MAP kinase family, extracellular regulated kinases (ERK), p38 and Jun N-terminal kinase. The NPC thus contains a spectrum of associated MAP kinases that suggests an intimate role for ERK and p38 in regulation of nuclear pore function., (© 2011 The Authors Journal of Cellular and Molecular Medicine © 2011 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.)

Diabetes mellitus is associated with abnormal cardiomyocyte Ca(2+) transients and contractile performance. We investigated the possibility that an alteration in inositol trisphosphate/phospholipase C (IP₃/PLC) signalling may be involved in this dysfunction. Phosphatidic acid stimulates cardiomyocyte contraction through an IP₃/PLC signaling cascade. We also tested a novel therapeutic intervention to assess its efficacy in reversing any potential defects. Diabetes was induced in Sprague-Dawley rats by streptozotocin treatment and maintained for an 8 week experimental period. Active cell shortening was significantly depressed in cardiomyocytes obtained from diabetic and insulin-treated diabetic rats in comparison to normal control animals. Perfusion of the cells with phosphatidic acid induced an increase in contraction of control rat cardiomyocytes whereas its effect was inhibitory in cells from streptozotocin-induced diabetic rats. Diabetic rats were also treated orally with vanadate administered in a black tea extract (T/V) for the 8 week period. T/V treatment resulted in a contractile response that was not different from cells of control animals. Furthermore, cardiomyocytes from T/V-treated animals exhibited significantly improved Ca(2+) transients in comparison to diabetic animals and exhibited a normalized response to phosphatidic acid perfusion. It is concluded that a T/V glycemic therapy is capable of preventing the defect in IP₃/PLC signaling that occurs in diabetes and can restore normal cardiac contractile function.

Cell proliferation within a primary atherosclerotic plaque is controversial. Identifying changes in cell cycle protein expression and the activities of their related kinases would provide valuable evidence of mitotic activity in the atherosclerotic lesion. Oxidized low-density lipoprotein has been shown to induce a significant increase in the total number of rabbit vascular smooth muscle cells in culture. In the present study, whole aortic cell extracts were harvested from rabbits fed a cholesterol-supplemented diet for eight weeks to induce modest plaque development, or 16 weeks to induce later, more severe plaque progression. Expression levels of cyclin A, cyclin-dependent kinase 4 (Cdk 4) and proliferating cell nuclear antigen were measured, as well as the activities of Cdk 4, Cdk 2 and Cdk 1. At both time points, the expression levels of cyclin A, Cdk 4 and proliferating cell nuclear antigen were significantly elevated. The activity of all three Cdks was also increased. There were no significant differences between moderate and more severe atherosclerosis. Surprisingly, tissues that neighboured the plaques, but did not show visible plaque formation on the vessel surface, also had significantly elevated cyclin A expression levels, but not as high as in the plaque areas. In conclusion, the primary atherosclerotic plaque exhibited elevated mitotic activity as shown by increased expression levels and activities of several cell cycle proteins. Expression levels were similar during moderate and severe atherosclerosis, and were even detected in nonatherosclerotic vascular tissue bordering the plaque.

Ischemia-reperfusion (IR)-induced cell apoptosis involves the activation of c-Jun NH2-terminal kinase (JNK). The activation of JNK requires the presence of scaffold proteins called JNK-interacting proteins (JIP), which bind several members of a signaling cascade for proper signaling specificity. In this study, the expression of scaffold proteins JIP1 and JIP3 and their roles in the regulation of JNK activity were investigated in simulated IR in a cell model (H9c2). JIP1 protein expression was significantly decreased, whereas JIP3 protein expression was increased in IR H9c2 cells. Adenovirus-induced overexpression of JIP1 reduced IR-induced JNK activity and apoptosis. Conversely, overexpression of JIP3 increased JNK activity and apoptosis following IR. Depletion of endogenous JIP1 by siRNA treatment increased the IR-induced JNK activity, whereas siRNA-mediated depletion of endogenous JIP3 inhibited JNK activity. These results suggest that JIP1 and JIP3 play important roles in the activation of JNK during simulated IR challenge in H9c2 cells.

Preventing the occurrence of cardiovascular disease (CVD) with nutritional interventions is a therapeutic strategy that may warrant greater research attention. The increased use of omega (&omega;)-3 fatty acids is a powerful example of one such nutritional strategy that may produce significant cardiovascular benefits. Marine food products have provided the traditional dietary sources of &omega;-3 fatty acids. Flaxseed is an alternative to marine products. It is one of the richest sources of the plant-based &omega;-3 fatty acid, alpha-linolenic acid (ALA). Based on the results of clinical trials, epidemiological investigations and experimental studies, ingestion of ALA has been suggested to have a positive impact on CVD. Because of its high ALA content, the use of flaxseed has been advocated to combat CVD. The purpose of the present review was to identify the known cardiovascular effects of flaxseed and ALA and, just as importantly, what is presently unknown.

Strong sero-epidemiologic, pathologic, and experimental evidence suggests that Chlamydophila pneumoniae (Cpn) infection may play a causative role in the development of atherosclerosis. Cpn is an obligate intracellular gram-negative bacterium that is responsible for 10% of cases of community-acquired pneumonia. In addition to its presence in the respiratory tract, live Cpn has been found within atherosclerotic plaques. Experimental findings have established Cpn's ability to infect vascular cells and elicit important atherogenic responses. Furthermore, Cpn infection can promote atherosclerotic development in different animal models. To date however, large-scale antibiotic clinical trials have not been effective in preventing major cardiovascular events. It is becoming apparent that Cpn undergoes a persistent state of infection, which is refractory to current chlamydial antibiotics. New treatment strategies that are effective toward acute and persistent forms of Cpn infection are needed in order to effectively eradicate the bacterium within the vascular wall. Possible therapeutics targets include Cpn-specific proteins and machinery directly involved in their survival, replication and maintenance. Alternatively, selectively targeting host cell pathways and machinery required for Cpn's actions in vascular cells also represent potential treatment strategies for atherosclerosis., (© 2010 The Authors Fundamental and Clinical Pharmacology © 2010 Société Française de Pharmacologie et de Thérapeutique.)

Diets rich in omega-3 polyunsaturated fatty acids are associated with decreased incidences of cardiovascular disease. The extent of incorporation and distribution of these beneficial fats into body tissues is uncertain. Rabbits were fed regular rabbit chow or a diet containing 10% ground flaxseed that is highly enriched with the omega-3 polyunsaturated fatty acid alpha-linolenic acid (ALA). The high-flaxseed diet resulted in an incorporation of ALA in all tissues, but mostly in the heart and liver with little in the brain. Docosahexaenoic and eicosapentaenoic acid levels were also selectively increased in some tissues, and the effects were not as large as ALA. Arachidonic acid and the ratio of omega-6/omega-3 fatty acids were decreased in all tissues obtained from the flax-supplemented group. Consumption of dietary flaxseed appears to be an effective means to increase ALA content in body tissues, but the degree will depend upon the tissues examined.

We investigated calpain activation in the heart during ischemia-reperfusion (I-R) by immunologically mapping the fragmentation patterns of calpain and selected calpain substrates. Western blots showed the intact 78 kDa large subunit of membrane-associated calpain was autolytically fragmented to 56 and 43 kDa signature immunopeptides following I-R. Under these conditions, the 78 kDa calpain large subunit from crude cytosolic fractions was markedly less fragmented, with only weakly stained autolytic peptides detected at higher molecular weights (70 and 64 kDa). Western blots also showed corresponding calpain-like degradation products (150 and 145 kDa) of membrane-associated alpha-fodrin (240 kDa) following I-R, but in crude myofibrils alpha-fodrin degradation occurred in a manner uncharacteristic of calpain. For control hearts perfused in the absence of ischemia, autolytic fragmentation of calpain and calpain-like alpha-fodrin degradation were completely absent from most subcellular fractions. The exception was sarcolemma-enriched membranes, where significant calpain autolysis and calpain-like alpha-fodrin degradation were detected. In purified sarcoplasmic reticulum membranes, RyR2 and SERCA2 proteins were also highly degraded, but for RyR2 this did not occur in a manner characteristic of calpain. When I-R-treated hearts were perfused with peptidyl calpain inhibitors (ALLN or ALLM; 25 micromol/L), calpain autolysis and calpain-like degradation of alpha-fodrin were equally attenuated by each inhibitor. However, only ALLN protected against early loss of developed pressure in hearts following I-R, with no functionally protective effect of ALLM observed. Our studies suggest calpain is preferentially activated at membranes following I-R, possibly contributing to impaired ion channel function implicated by others in I-R injury.

Despite its use in our diet for hundreds of years, hempseed has surprisingly little research published on its physiological effects. This may have been in the past because the psychotropic properties wrongly attributed to hemp would complicate any conclusions obtained through its study. Hemp has a botanical relationship to drug/medicinal varieties of Cannabis. However, hempseed no longer contains psychotropic action and instead may provide significant health benefits. Hempseed has an excellent content of omega-3 and omega-6 fatty acids. These compounds have beneficial effects on our cardiovascular health. Recent studies, mostly in animals, have examined the effects of these fatty acids and dietary hempseed itself on platelet aggregation, ischemic heart disease and other aspects of our cardiovascular health. The purpose of this article is to review the latest developments in this rapidly emerging research field with a focus on the cardiac and vascular effects of dietary hempseed.

The Na(+)/Ca(2+) exchanger (NCX) is proposed to be an important protein in the regulation of Ca(2+) movements in the heart. This Ca(2+) regulatory action is thought to modulate contractile activity in the heart under normal physiological conditions and may contribute to the Ca(2+) overload that occurs during ischemic reperfusion challenge. To evaluate these hypotheses, adult rat cardiomyocytes were exposed to an adenovirus that codes for short hairpin RNA (shRNA) targeting NCX gene expression through RNA interference. An adenovirus transcribing a short RNA with a scrambled nucleotide sequence was compared with the NCX-shRNA nucleotide sequence and used as a control. Freshly isolated rat cardiomyocytes were infected with virus for 48 h before examination. Cardiomyocytes maintained their characteristic morphological appearance during this short time period after isolation. NCX expression was inhibited by up to approximately 60% by the shRNA treatment as determined by Western blot analysis. The depletion in NCX protein was accompanied by a significant depression of NCX activity in shRNA-treated cells. Ca(2+) homeostasis was unaltered in the shRNA-treated cells upon electrical stimulation compared with control cells. However, when cardiomyocytes were exposed to a simulated ischemic solution, NCX-depleted cells were significantly protected from the rise in cytoplasmic Ca(2+) and damage that was detected in control cells during ischemia and reperfusion. Our data support the role for NCX in ischemic injury to the heart and demonstrate the usefulness of altering gene expression with an adenoviral-delivery system of shRNA in adult cardiomyocytes.

Chlamydophila pneumonia (C. pneumonia) infection has been associated with the progression of atherosclerosis. It remains unclear, however, whether C. pneumoniae in the absence of an immune response can alone initiate atherogenic events within a complex vessel environment. Left anterior descending coronary arteries isolated from porcine hearts were dissected and placed in culture medium for 72 hours before infection with C. pneumoniae. C. pneumoniae replicated within the arterial wall for the duration of the experiment (up to 10 days). A significant increase in chlamydial-HSP60 protein expression from day 2 to 10 post-infection (pi) indicated the presence of metabolically active C. pneumonia within infected vessels. Significant arterial thickening in infected coronary segments was observed by a considerable decrease in the ratio of lumen to total vessel area (48 +/- 3% at day 4 pi versus 23 +/- 3% at day 10 pi) and a significant increase in the ratio of media to luminal area (113 +/- 16% at day 4 pi versus 365 +/- 65% at day 10 pi). Structural changes were accompanied by an up-regulation of host HSP60 and proliferating cell nuclear antigen expression levels. Immunohistochemical staining confirmed proliferating cell nuclear antigen expression to be primarily localized within smooth muscle cells of the medial area. These results demonstrate that C. pneumoniae infection can stimulate arterial thickening in a complex vessel environment without the presence of a host immune response and further supports the involvement of HSP60 in this action.

Epidemiological evidence has associated dietary trans-fatty acids (TFAs) with coronary heart disease. It is assumed that TFAs stimulate atherosclerosis, but this has not been proven. The purpose of this study was to determine the effects of consuming 2 concentrations of TFAs obtained from commercially hydrogenated vegetable shortening on atherosclerotic development in the presence or absence of elevated dietary cholesterol. Low-density lipoprotein receptor-deficient mice were fed 1 of 7 experimental diets for 14 weeks: low regular fat (LR), low trans-fat (LT), regular high fat, high trans-fat (HT), or a diet containing 2% cholesterol with low regular fat (C + LR), low trans-fat (C + LT), or high trans-fat (C + HT). The extent of lesion development was quantified by en face examination of the dissected aortae. Dietary cholesterol supplementation significantly elevated serum cholesterol levels. Surprisingly, this rise was partially attenuated by the addition of TFAs (C + LT and C + HT) in the diet. Serum triglyceride levels were elevated with the higher-fat diets and with the combination of trans-fat and cholesterol. Animals consuming TFAs in the absence of dietary cholesterol developed a significantly greater extent of aortic atherosclerotic lesions as compared with control animals (LT > LR and HT > regular high fat). Atherosclerotic lesions were more extensive after cholesterol feeding, but the addition of TFAs to this atherogenic diet did not advance atherosclerotic development further. In summary, TFAs are atherogenic on their own; but they do not stimulate further effects beyond the strongly atherogenic effects of dietary cholesterol.

Functional foods and nutraceuticals are becoming popular alternatives to pharmacological treatments by providing health benefits and (or) reducing the risk of chronic diseases. Flaxseed is a rich source of 3 components with demonstrated cardioprotective effects: the omega-3 fatty acid alpha-linolenic acid (ALA), dietary fibre, and phytoestrogen lignans. Multiple clinical dietary intervention trials report that consuming flaxseed daily can modestly reduce circulating total cholesterol (TC) by 6%-11% and low-density lipoprotein (LDL) cholesterol by 9%-18% in normolipemic humans and by 5%-17% for TC and 4%-10% for LDL cholesterol in hypercholesterolemic patients, as well as lower various markers associated with atherosclerotic cardiovascular disease in humans. Evidence to date suggests that the dietary fibre and (or) lignan content of flaxseed provides the hypocholesterolemic action. The omega-3 ALA found in the flaxseed oil fraction also contributes to the antiatherogenic effects of flaxseed via anti-inflammatory and antiproliferative mechanisms. Dietary flaxseed may also protect against ischemic heart disease by improving vascular relaxation responses and by inhibiting the incidence of ventricular fibrillation.

It is becoming increasingly evident that poor nutrition plays an important role in inducing cardiovascular disease. Just as importantly, data now support the contention that appropriate nutritional interventions may have just as important an effect in preventing or delaying the appearance of cardiovascular disease. If this is indeed true, then it is critical that these advances in our knowledge of the effects of nutritional interventions be translated into effective strategies to combat cardiovascular disease. It is argued in this paper, with a few specific examples, that the translation of nutritional interventions can provide powerful approaches to alleviating the clinical challenges currently facing us today in the cardiovascular field. Furthermore, the value-added economic advantages of translating nutritional strategies on a wide scale into the public become another intriguing argument to further support investigations in this growing field.

Proteins enter the nucleus through the nuclear pore complex. Once in the nucleus, some proteins, such as transcriptional regulators, can turn genes on or off, and change the composition of the cell and its function to meet the demands of its environment. This process of protein import into the nucleus is highly controlled and regulated by the expression or function of single cargoes, transport receptors, or the transport channels themselves. Thus, these components of the import process have an impact on transport capacity, which subsequently affects gene expression, signal transduction, and cell growth and development. With such a key position in the process of cell growth, it is reasonable to hypothesize that alterations in nuclear protein transport may play an important role in pathological cell conditions that have abnormal cell growth as a central feature. Indeed, there are now sufficient data to demonstrate that alterations in nuclear protein transport participate in alterations in cell proliferation and hypertrophy. Further study is needed to provide definitive proof that changes in nuclear protein import directly participate in the pathogenesis of diseases such as hypertension, atherosclerosis, cancer, viral infection, and diabetes. However, the data to date have, on select occasions, led to a clear association of alterations in nuclear transport with disease states. Furthermore,this research has led to the important identification of new targets within the process of nuclear protein import that hold therapeutic promise to inhibit viral replication, to improve drug delivery during cancer therapy, and, in general, to modify cell growth and viability during disease conditions.

We investigated the effects of a high-fructose (HF) diet on cardiovascular risks in Sprague-Dawley rats. Twelve rats were randomly assigned to standard chow or HF diet for 20 weeks. Systolic blood pressure and circulating insulin, total cholesterol, and triacylglycerol levels were significantly higher in the HF group. Aortic sections appeared normal, but liver sections from the HF group showed lipid accretion, mild inflammation, and bile pigmentation. Liver samples from the HF group showed significantly higher total lipid levels and changes in fatty acid profile. Levels of 16:0, cis-9-18:2, cis-11-20:1, cis-13-20:1, cis-11-20:2 and 24:0 were significantly raised in the phospholipid fraction. Lower levels of cis-11-18:1, cis-9-18:2, and cis-11-20:1 and increased levels of 16:1, cis-9-18:1, and cis-13-20:1 were found in the non-esterified fatty acid fraction. HF-feeding resulted in significant reductions in plasma levels of certain inflammatory biomarkers. HF intake over time may negatively impact cardiovascular health and liver function in rats.

Oxidized low density lipoprotein (oxLDL) plays an important role in the development of atherosclerosis partly through an action on cell proliferation and cell apoptosis. Nuclear protein import (NPI) is critical in regulating gene expression, transcription, and subsequently cell proliferation and apoptosis. The aim of this study was to determine if exposure of vascular smooth muscle cells (VSMC) to oxLDL affects cell growth by inducing alterations in NPI and nuclear pore density. VSMC were exposed for different times to oxLDL. Cells were then injected with a protein import substrate (Alexa488-BSA-NLS) to visually monitor nuclear transport with the confocal microscope. The effect of MAPK inhibitors (SB203580 and PD98059) was investigated and western immunoblottings were also performed. Shorter exposure times of VSMC to oxLDL, but not to native LDL, significantly increased NPI, nuclear pore expression (p62), PCNA expression, and cell number. These changes occurred through an ERK MAPK-dependent mechanism. However, longer exposures to oxLDL decreased NPI, nuclear pore expression, and increased apoptosis marker (cleaved PARP) expression through a p38 MAPK-dependent mechanism. We conclude that limited exposure to oxLDL may influence cell proliferation and apoptosis through an action on nucleocytoplasmic trafficking. The nucleus and NPI may represent a novel therapeutic target to control diseases like atherosclerosis that have changes in cell growth as a central feature.