Endogenously, VEGF initiates angiogenesis, then later Angiopoietin (Ang)-1 matures vessels. We hypothesized that multigene therapy of VEGF before Ang1 to ischemic hindlimb tissue would result in persistent angiogenesis. At 2, 4 and 8 wks after inducing ischemia, blood flow was assessed by contrast-enhanced ultrasound. Animals were treated with VEGF at 2 wks, VEGF/Ang1 at 2 wks, or VEGF at 2 wks and Ang1 at 4 wks. In untreated controls, blood flow remained reduced. After VEGF delivery, resting flow and vessel density increased; however, flow reserve remained reduced, and vasculature was capillary-rich and eventually regressed. After VEGF/Ang1 co-delivery, flow increased marginally, flow reserve improved and vascular architecture remained normal. After separated VEGF and Ang1 delivery, flow, vessel density and flow reserve increased and were sustained, while vascular architecture remained normal. In conclusion, temporally separated VEGF and Ang1 delivery promotes sustained angiogenesis and improved vessel functionality.

Endothelial progenitor cells (EPCs) have reduced neovascularization capacity in the context of coronary artery disease (CAD) or cardiac risk factors (RFs). Since, endothelial NO synthase (eNOS) is critical to normal EPC function, we hypothesized that bone marrow cells (BMCs) from rats with RFs and EPCs from humans with CAD and/or RFs show dramatically reduced neovascularization capacity in vitro and in vivo, which can be reversed by eNOS overexpression. BMCs were isolated from rat models of type II diabetes and the metabolic syndrome, and we showed a significant reduction in their ability to stimulate neovascularization in vitro and in vivo. In humans, we isolated circulating ‘early EPCs’ from healthy subjects and patients with CAD and RFs, and transduced them using lentiviral vectors containing either eNOS or GFP (sham). EPCs from patients had reduced in vitro migration in response to SDF-1 or VEGF, which was reversed by eNOS-transduction. In co-culture with human umbilical vein endothelial cells (HUVECs) on Matrigel, eNOS-transduced EPCs contributed to increased and more complex angiogenic tube formation compared to sham-transduced cells. Human EPCs from patients were ineffective in enhancing ischemic hind limb neovascularization and perfusion in a nude mouse, whereas eNOS-transduced EPCs resulted in a significant improvement compared to sham-transduced cells. In a swine model of acute myocardial infarction (MI), eNOS- and non-transfected BMCs both increased left ventricular function compared to sham. However, there was no benefit to eNOS overexpression in this model. Various differences in the models and procedures may explain the incongruous results obtained. Taken together, these results show that eNOS overexpression significantly improves the neovascularization capacity of EPCs of human subjects with CAD and RFs and could represent an effective adjunctive approach for the improvement of autologous cell therapies for cardiovascular disease.

An oxidative stress in the form of H2O2 exposure previously has been shown to cause a transient increase in NO??oduction and a chronic increase in eNOS protein levels. Nevertheless, oxidative stress can cause an uncoupling of catalytic activity resulting in decreased NO??d increased O2??roduction from eNOS. This uncoupling seems to be mediated predominantly by oxidation of tetrahydrobiopterin (BH4), an eNOS required cofactor. To study how these phenomena regulate the physiological balance of reactive oxygen species (ROS), H2O2-induced NO??oduction was measured in bovine aortic endothelial cells (BAECs) using an NO??ecific electrode. Following H2O2 exposure, NO??ncentrations initially increased; however, if cells were challenged a second time with H2O2, the increase in NO??oduction was attenuated. We postulated that the decline in NO??oduction after H2O2 exposure resulted from BH4 oxidation and tested this by supplementing cells with BH4 prior to the second H2O2 exposure. This resulted in a recovery of NO??oduction. Since H2O2 also activates NADPH oxidase to produce superoxide (O2?? we tested whether the decrease in NO??oduction during the second H2O2 exposure could be explained by increased NADPH oxidase-dependent oxygen free radical production, including O2??peroxynitrite (ONOO-), and hydroxyl radicals (??. A reduction in H2O2-induced NO??lease was prevented in apocynin-and PEG-SOD-treated cells and in p47phox-knockout mouse aortic endothelial cells (MAECs), which lack a critical subunit of the NADPH oxidase. These results suggest that O2??roduced by NADPH oxidase leads to eNOS dysfunction. Scavenging ONOO- resulted in a full recovery of NO??oduction, and scavenging ??resulted in a partial recovery of NO??oduction. This implies roles for these O2??erivatives in the reduced NO??sponse to repeated H2O2 exposures.

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Background: In Sweden and Northern Europe, cardiovascular disease mortality rates are high. The clinical picture in the Western world is dominated by lifestyle diseases in which individual behavior and attitudes have a significant impact on the health effect. In the society cardiovascular disease is seen as an illness factor and contribution to disability. Conditions for a good life are not only good health also factors such as intimate relationships and meaningful work which affect the person's quality of life. Aim: Lifestyle changes and quality of life for patients, regarding cardiovascular disease. Method: A literature review was made. Eight articles, quantitative and qualitative were analyzed. The analysis revealed three themes and four subthemes. Results: Through interventions bodily- and behavioral change occurred, for example weightloss, better cholesterol- and bloodpressure levels and increased physical activity. Respondents also had better quality of life. Great importance was laid on education and information about different lifestyle changes. On the contrary, the nursing staff was careless with the documentation. Conclusion: Lifestyle changes such as smoking cessation, increased physical activity, reducing obesity and improving dietary habits and psychosocial factors such as reduced stress and depression, have a positive impact on the health of cardiovascular disease. Because these changes should not affect patients' quality of life, the nurse's communication and information are important. It's also important to combine good lifestyle changes with good quality of life, as adherence then is better. The nurse has to consider the patients whole life situation.

Background: Previous literature has found mixed results concerning the relationship between depression, and anxiety, and length of hospital stay among cardiac surgical patients. Given the high prevalence of these psychiatric illnesses and cardiovascular disease in Canada, a better understanding of the relationship between these variables has the potential to influence medical and psychiatric outcomes for countless individuals. Objectives: The objectives of this manuscript style thesis are to (a) describe the prevalence of mild and moderate-to-severe symptoms of depression and anxiety disorders in a sample of cardiac patients (Manuscript 1) and (b) analyze the effects of these symptoms on post-operative length of stay while controlling for potential confounding variables (Manuscript 2). Methods: This secondary analysis used data collected from a consecutive series of consenting patients attending Foothills Hospital Pre-operative Assessment Clinic (August 1998-March 2002). Patients completed the Zung Self-Rating Depression and Anxiety scales, and a questionnaire assessing potential confounders. Manuscript 1: Prevalence values and 95% intervals were calculated for mild and moderate-to-severe depression and anxiety while logistic regression was used to determine predictors of these conditions. Manuscript 2: The relationship between symptoms of depression, anxiety and length of stay was analyzed using multiple linear regression. Results: Manuscript 1: We estimated that moderate-to-severe symptoms of depression and anxiety were present in 10.66% and 3.42%, respectively. Mild depression (21.90%) and anxiety (32.89%) were also present. Common predictors of both conditions included sex, general health, and a recent myocardial infarction. Depression was further associated with co-morbid illness, as was type of surgery with anxiety. Manuscript 2: Patients with depression experienced a significant increase in length of stay compared to mentally healthy patients. Age, general health, type of surgery and education also predicted hospital stay, while anxiety did not. Conclusions: Manuscript 1: The prevalence of depression and anxiety in our sample demonstrates the need to address the burden of psychiatric illness in this population. Predictors of these disorders may assist in determining risk groups that would benefit most from psychiatric testing and interventions. Manuscript 2: The elevated length of stay observed among patients with depression supports the implementation of screening and treatment in this population. / Thesis (Master, Community Health & Epidemiology) -- Queen's University, 2010-11-03 19:01:58.445

It is becoming increasingly evident that the development of atherosclerotic coronary heart disease (CHD) can largely be regulated by lifestyle and dietary choices. The type of fatty acids regularly consumed may promote or prevent atherogenesis. Flaxseed, the richest plant source of the omega-3 fatty acid alpha-linolenic acid (ALA) is thought to protect against atherosclerotic disease. However, the mechanism(s) by which flaxseed exerts these anti-atherogenic effects requires further investigation. Alternatively, there are dietary fatty acids that are thought to induce significant deleterious effects upon our cardiovascular health. Epidemiological evidence associates dietary trans fatty acids (TFAs) with atherosclerotic CHD. This evidence has largely focused on the main source of TFAs in the North American diet, industrially hydrogenated vegetable shortening (iTFAs). It is assumed that TFAs stimulate atherosclerosis but the only studies to date have shown no effect of TFAs on atherosclerosis. Even less is known of the impact of naturally occurring TFAs from dairy and meat products of ruminant animals (rTFAs) on atherosclerotic disease. We investigated the effects of flaxseed supplementation on atherosclerosis and vascular function in two animal models, the hypercholesterolemic rabbit and the cholesterol fed, low density lipoprotein receptor (LDLr-/-) deficient mouse. New Zealand White rabbits and LDLr-/- mice were fed a diet containing flaxseed in the absence or presence of dietary cholesterol for a period of 6 to 24 weeks. We found that dietary flaxseed inhibits the atherogenic effects of a high cholesterol diet in both animal models. The anti-atherogenic effect was achieved in the mouse model through a capacity to lower circulating cholesterol levels and at a cellular level by inhibiting cell proliferation and inflammation. This reduction is also associated with an improved vascular relaxation response as demonstrated in the rabbit model. We also investigated the effects of consuming TFAs from two sources, industrially hydrogenated iTFAs rich in elaidic TFA (C18:1t-9) or naturally-occurring ruminant rTFAs rich in vaccenic TFA (C18:1t-11), on atherosclerotic development in the LDLr-/- mouse in the presence or absence of elevated dietary cholesterol. Our results demonstrate that consuming iTFAs dose dependently initiates atherosclerotic development but not beyond the effects of dietary cholesterol alone. However, consuming rTFAs rich in vaccenic acid protects against hyperlipidemia and atherosclerosis in the presence or absence of dietary cholesterol. The effects of combining dietary flaxseed and iTFAs in the diet were also examined in this model. Adding whole ground flaxseed or flaxseed oil (ALA) to diets containing low and high doses of iTFAs completely prevented atherosclerotic development in the absence of dietary cholesterol. Flaxseed was also able to partially prevent atherosclerosis caused by iTFAs and cholesterol. Our results suggest that the omega-3 ALA fatty acid rich content of flaxseed is mainly responsible for the anti-atherogenic effects of flaxseed. Our results highlight potential mechanisms for the beneficial effects of dietary flaxseed and the mixed effects of TFAs on cardiovascular health and underscore the need for further basic and clinical investigations.

Considerable interest has focused on the influence of dietary fat quality on cardiovascular disease (CVD) risk. Increasingly, novel dietary oils rich in oleic acid and alpha-linolenic acid (ALA) are being developed and marketed with an aim to improve fatty acid intakes and reduce CVD risk. The objective of this research was to investigate the efficacy of high-oleic canola oil (HOCO) alone, or blended with flaxseed oil (FXCO), on traditional and emerging clinical biomarkers of CVD risk. An additional aim was to study the influence of dietary and genetic factors on metabolism of 13C-ALA to long-chain PUFA. Using a diet-controlled randomized crossover design, thirty-six hypercholesterolaemic subjects consumed three isoenergetic diets for 28 days each containing ~36% energy from fat, of which 70% was provided by HOCO, FXCO, or a Western dietary fat blend (WD; control). Endpoint measures revealed reductions (P<0.001) in serum lipid concentrations, including a 7.4% and 15.1% decrease in LDL-cholesterol after HOCO and FXCO diets, respectively, as compared with the WD control. Moreover, a reduction (P=0.023) in plasma E-selectin concentration was found after the FXCO diet compared with the WD control. Consumption of the dietary oils failed to alter whole-body fat oxidation or energy expenditure, nor lead to alterations in body composition. FXCO diet increased (P<0.001) plasma ALA ~5-fold, EPA ~3-fold, and DPA ~1.5-fold, but did not modulate DHA levels compared with the WD control. At 24 and 48 hours the amount of administered 13C-ALA recovered as plasma 13C-EPA and 13C-DPA was lower (P<0.001) after FXCO diet compared with HOCO and WD diets, suggesting decreased ALA conversion efficiency with very high intakes of dietary ALA. No difference in plasma 13C-DHA enrichment was observed across diets. Moreover, minor alleles of selected single nucleotide polymorphisms in the FADS1/FADS2 gene cluster were associated with reduced (P<0.05) plasma fatty acid compositions and apparent conversion of 13C-ALA. However, increased consumption of ALA in the FXCO diet compensated for lower levels of EPA in minor allele homozygotes. Taken together, substitution of dietary fats common to WD with both HOCO and FXCO represents an effective strategy to target several biomarkers for CVD risk reduction.

This dissertation investigates the role of limonoids in inflammation to reduce risk of breast cancer and cardiovascular disease. Radical scavenging activity and apoptotic effects of extracts from lemon seeds were investigated in human breast adenocarcinoma (MCF-7) cells and non-malignant breast (MCF-12F) cells. The MeOH:water (80:20) extract showed the highest (29.1%, P < 0.01) inhibition of MCF-7 cells without affecting the non-malignant breast cells. Further, the purified and modified limonoids were screened for their cytotoxicity on estrogen receptor (ER)-positive (MCF-7) or ER-negative (MDA-MB-231) human breast cancer cells. The MCF-7 cell was more susceptible to tested limonoids. Although most of limonoids induced anti-aromatase activity, the inhibition of proliferation was not related to the anti-aromatase activity. On the other hand, the anti-proliferative activity was significantly correlated with the level of caspase-7 activation by limonoids. The next study investigated the mechanism of anti-breast cancer and anti-aromatase activities of obacunone through inhibition of MCF-7 cell proliferation without affecting non-malignant breast cells. Treatment with obacunone resulted in an increased G1 cell cycle arrest and induction of apoptosis. Exposure of MCF-7 breast cancer cells to obacunone down-regulated expression of inflammatory molecules including nuclear factor-kappa B (NF--2 (COX-2). Furthermore, potential of obacunone on inhibition of COX-2 and NF-the p38 mitogen-activated protein (MAP) kinase was also investigated. In the final study, nomilin was the most potent natural inhibitor for p38 MAP kinase activity in human aortic smooth muscle cells indicating that a seven-membered A ring with acetoxy group, present in nomilin, seems to be essential for its inhibitory activity on p38 MAP kinase. The possible mechanism of nomilin for prevention of cardiovascular disease was determined. Pre-treatment with nomilin resulted in significant inhibition of TNF- induced HASMCs proliferation. The anti-proliferative activity of nomilin is due to apoptosis through mitochondrial dependent pathway.

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