Patients with rheumatoid arthritis (RA) have a shorter life span than the general population. An increased death due to cardiovascular disease (CVD) has been reported. RA is characterized by synovitis and joint destruction accompanied by an acute phase reaction and systemic features. The present work investigates the epidemiology of CVD in patients with RA in the county of Västerbotten and the influence of inflammation on lipid metabolism and haemostasis. In a retrospective cohort study on 606 RA patients, the overall mortality was significantly higher than in the general population, with an excess death rate for CVD and for ishemic heart diseae (IHD) in both sexes. Multiple Cox regression, showed that male sex, higher age at disease onset and cardiovascular event increased the risk for death. Male sex, high age at disease onset and hypertension increased the risk for cardiovascular event. Diabetes mellitus, treatment with corticosteroids, disease modifying antirheumatic drugs and postmenopausal estrogen neither influenced survival nor the risk of cardiovascular event. In 93 patients with active RA, the levels of cholesterol, high density- (HDL) and low density (LDL) lipoprotein cholesterol were significantly lower, and Lipoprotein(a) was significantly higher compared to controls. In a follow-up on 53 patients, a relation between the change of Lp(a) and acute phase proteins was found only in patients with high levels of Lp(a). Preheparin lipoprotein lipase (LPL) activity and mass were significantly decreased in 17 postmenopausal women with active RA. Preheparin LPL mass correlated inversely to several acute phase proteins and interleukin-6. Low levels of LPL mass may implicate increased hepatic clearence but also increased macrophage ingestion of lipoproteins via the LDL receptor-related protein (LRP). Haemostasis of the circulation was investigated in 74 of the 93 patients with active RA. In patients with extraarticular disease, the release of tissue plasminogen activator (tPA) was significantly decreased, and its inhibitor (PAI-1) was significantly increased compared to patients with nonsystemic disease, implicating hypofibrinolysis. In a two year follow-up, patients with thromboembolic events had significantly elevated levels of von Willebrand factor, PAI-1, triglycerides and haptoglobin compared to event-free patients. In 29 RA patients and 18 spondylarthropathy patients with gonarthritis, radiological joint destruction correlated to PAI-1 antigen in synovial fluid and, inversely, to plasminogen. A relationship between activation of fibrin degrading proteolytic enzymes and joint destruction was implicated. In conclusion, several processes involved in lipid metabolism and haemostasis are influenced in active RA. In view of the increased death rate due to CVD, an efficient control of inflammation should be important, not only for reducing joint destruction, but also for reducing systemical atherogenic and thrombogenic effects. / <p>s. 1-54: sammanfattning, s. 55-133: 6 uppsatser</p> / digitalisering@umu.se

Cardiovascular disease is the main cause of death in the United States. Although it is recognized that moderate intensity long-term exercise can decrease the chances of dying from cardiovascular disease by favorably modifying risk factors such as hypertension, obesity, hyperlipidemia, and insulin resistance, physical activity also enhances longevity by mechanisms independent of these risk factors. This review briefly summarizes what is known about the inflammatory nature of atherosclerosis and how long-term aerobic exercise can reduce the atherogenic activity of endothelial cells, blood mononuclear cells, and adipose tissue.

Brazil nut (Bertholletia excelsa, Lecythidaceae family) is the richest known food in selenium. Its consumption has demonstrated efficient in improving the lipid profile and the plasmatic selenium levels as well as to increase the activity of glutathione peroxidase (GPx) enzyme in humans. Thus, this study aims at evaluating the metabolic effects of a single portion of Brazil nut intake in healthy humans. It is a cross-over randomized controlled clinical trial with professedly healthy adults. A group of 10 volunteers were part of the study; they were from both sexes, coming from Santa Maria/RS, region. The volunteers who accept to take part in the study have consumed portions with different Brazil nut concentration, they were divided into four groups: 0, 5, 20 or 50 g. Each group collected blood before the nuts consumption and also 1, 3, 6, 9, 24, 48 hours, 5 and 30 after the Brazil nuts consumption. We then evaluated the oxidative stress markers with activity of the GPx and δ-aminolevulinic acid dehydratase enzymes, the selenium plasmatic levels, inflammatory markers such as pro-inflammatory cytokines: the tumor necrosis factor (TNF-α), interferon gamma (INF-γ) and interleukin (IL) 1,6 and 8; and the anti-inflammatory interleukin IL-10. Besides that, it was also evaluated the blood count and the hepatic and renal markers. In the Brazil nut we analyzed the selenium concentration, fatty acids and the presence of flavonoids and phenolic compounds. Volunteers biochemical parameters were normal. The results demonstrated that Brazil nut intake significantly increased selenium plasmatic levels for the volunteers who consumed 20 and 50 g of Brazil nuts in relation to basal levels with the higher peak occurring 6 hours after the Brazil nut consumption. However, the consumption of portions with different selenium concentrations for 30 days was not enough to increase the GPx erythrocyte levels activity. The higher plasmatic selenium peak was observed 6 hours after the nuts consumption. In the same way, it was observed that the volunteers who consumed a portion of 20 or 50g of Brazil nut presented improvement in the lipid profile with reduction of total cholesterol and LDL-c and, an increase of HDL-c also 6 hours after consuming the nuts until the 30th day. And furthermore, the groups that consumed a portion of 20 or 50g of Brazil nut had their serum concentration of IL-1, TNF-α, INF-γ decreased and the anti-inflammatory interleukin IL-10 increased, starting from 9 hours after consuming the nuts until the 30th day. It was possible to observe that the consumption of a 20 or 50g portion of Brazil nut in healthy humans during a 30 days period has improved the lipid profile and the inflammatory parameters for these volunteers. We can also point that the interaction of Brazil nut compounds may have contributed for the achieved results. Nevertheless, although this study demonstrated benefic effects for the consumption of a 20 or 50g of Brazil nut in a 30 days period, it is precipitated to change the recommendation of a daily 5g Brazil nut portion. Further studies are necessary to better clarify these effects. / A castanha do Brasil (Bertholletia excelsa, família Lecythidaceae) é o alimento mais rico em selênio conhecido até hoje. O seu consumo já se mostrou eficiente em melhorar o perfil lipídico e os níveis plasmáticos de selênio, além de aumentar a atividade da enzima glutationa peroxidase (GPx) em humanos. Desta forma, o objetivo deste estudo foi avaliar os efeitos metabólicos do consumo de uma única porção de castanha do Brasil ao longo de 30 dias em humanos saudáveis. Tratou-se de um ensaio clínico randomizado controlado, do tipo cross-over realizado com adultos declaradamente saudáveis. Fizeram parte do estudo 10 voluntários, de ambos os sexos, provenientes da região de Santa Maria, RS. Os voluntários que aceitaram participar da pesquisa consumiram uma porção de diferentes concentrações de castanha do Brasil, sendo divididos em quatro grupos: 0, 5, 20 ou 50 g. Foi Cada grupo coletou sangue antes do consumo das castanhas e 1, 3, 6, 9, 24, 48 horas, 5 e 30 dias após o consumo de castanhas. Foram avaliados os marcadores do estresse oxidativo como atividade das enzimas GPx e δ-aminolevulinato desidratase, níveis plasmáticos de selênio, marcadores inflamatórios como citocinas pró-inflamatórias: fator de necrose tumoral (TNF-α), interferon gama (INF-γ), interleucinas (IL) 1, 6 e 8; e a interleucina anti-inflamatória IL-10. Além disso, foram avaliados o hemograma, marcadores hepáticos e renais. Na castanha do Brasil foram analisadas concentrações de selênio, ácidos graxos, presença de compostos fenólicos e flavonoides. Os parâmetros bioquímicos dos voluntários se encontraram dentro da normalidade. Os resultados demonstraram que o consumo de castanha do Brasil aumentou significativamente os níveis plasmáticos de selênio nos voluntários que consumiram 20 e 50 g de castanhas em relação aos níveis basais, tendo o maior pico nas 6 h após o consumo das castanhas. Contudo, o consumo de uma porção de diferentes concentrações de selênio durante 30 dias não foi suficiente para aumentar a atividade dos níveis eritrocitários da GPx. Do mesmo modo, foi observado que os voluntários que consumiram uma porção de 20 ou 50 g de castanha do Brasil apresentaram melhora do perfil lipídico, com diminuição do colesterol total e LDL-c e aumento do HDL-c também a partir de 6 h após o consumo até o 30º dia. Além disso, os grupos que consumiram uma porção de 20 ou 50 g de castanha do Brasil tiveram concentrações séricas da IL-1, TNF-α, INF-γ diminuídas e a interleucina anti-inflamatória IL-10 aumentada, a partir de 9h após o consumo de castanhas até o 30º dia. Pode-se observar que o consumo de uma porção de 20 ou 50 g de castanha do Brasil em humanos saudáveis em um período de 30 dias melhorou o perfil lipídico e os parâmetros inflamatórios desses voluntários. Além disso, pode-se evidenciar que a interação dos compostos da castanha pode ter contribuído para os resultados apresentados. No entanto, apesar do presente estudo mostrar efeitos benéficos do consumo de uma porção de 20 ou 50 g de castanha do Brasil em 30 dias, ainda é muito precipitado modificar a recomendação de uma porção de 5 g de castanha diária. Mais estudos são necessários para esclarecer melhor estes efeitos.

Doctor of Philosophy / Department of Human Nutrition / Denis M. Medeiros / Laman Mamedova / The internalization of aggregated low-­density lipoprotein (agLDL) may involve the actin cytoskeleton in ways that differ from the endocytosis of soluble LDL. Based on previous findings the P2Y[subscript]2 receptor (P2Y[subscript]2R) mediates these effects through interaction with filamin‐A (FLN‐A), an actin binding protein. Our findings also showed that uridine 5’‐ triphosphate (UTP), a preferential agonist of the P2Y[subscript]2R, stimulates the uptake of agLDL, and increases expression of low‐density lipoprotein receptor related protein 1 (LRP 1) in cultured mouse vascular smooth muscle cells (SMCs). The strategy of this research was to define novel mechanisms of LDL uptake through the modulation of the actin cytoskeleton in order to identify molecular targets involved in foam cell formation in vascular SMCs. For this project, we isolated aortic SMCs from wild type (WT) and P2Y[subscript]2R‐/‐ mice to investigate whether UTP and the P2Y[subscript]2R modulate expression of LRP 1 and low‐density lipoprotein receptor (LDLR). We also investigated the effects of UTP on uptake of DiI‐labeled agLDL in WT and P2Y[subscript]2R‐/‐ vascular SMCs. For LRP1 expression, cells were stimulated in the presence or absence of 10 [mu]M UTP. To determine LDLR mRNA expression, and for agLDL uptake, cells were transiently transfected for 24 h with cDNA encoding hemagglutinin-­tagged (HA-­tagged) WT P2Y[subscript]2R or a mutant P2Y[subscript]2R that does not bind FLN‐A, and afterwards treated with 10 [mu]M UTP. Total RNA was isolated, reversed transcribed to cDNA, and mRNA relative abundance determined by RT-­PCR using the delta-­delta Ct method with GAPDH as control gene. Results show SMCs expressing the mutant P2Y[subscript]2R that lacks the FLN‐A binding domain exhibit 3‐fold lower LDLR expression than SMCs expressing the WT P2Y[subscript]2R. There was also decrease in LRP1 mRNA expression in response to UTP in P2Y[subscript]2R‐/‐ SMCs compared to WT. Actinomycin‐D (20 [mu]g/ml) significantly reduced UTP-­induced LRP1 mRNA expression in P2Y[subscript]2R‐/‐ SMCs (P < 0.05). Compared to cells transfected with mutant P2Y[subscript]2R, cells transfected with WT P2Y[subscript]2R showed greater agLDL uptake in both WT VSMC and P2Y[subscript]2R-­/-­ cells. Together these results show that both LRP 1 and LDLR expressions are dependent on an intact P2Y[subscript]2R, and P2Y[subscript]2R/ FLN‐ A interaction is necessary for agLDL uptake.