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Aims: LDL oxidation plays an important role in the initiation and progression of atherosclerosis. HDL impedes oxidation, glycation and glycoxidation in vitro and there is evidence to suggest paraoxonase-1 (PON1) plays an important role in this. 1. In patients with dyslipidaemia treated with statins, I assessed the relationship of serum PON1 activity with in vitro HDL antioxidant capacity, susceptibility of LDL to oxidation and the protection offered by HDL. 2. I studied the effect of the presence and severity of obstructive sleep apnoea (OSA) in morbidly obese patients on HDL anti-oxidant and anti-inflammatory functions. 3. I investigated the influence of extended release niacin/ laropiprant (ERN/LRP) versus placebo in patients who had persistent dyslipidaemia despite receiving high doses of potent statins. I assessed the effect of ERN/LRP on mediators of vascular inflammation and HDL's in vitro anti-oxidant function. Methods: 1. LDL isolated from dyslipidemic patients was incubated with and without HDL, in the presence of Cu2+. Similarly isolated HDL was incubated alone. Lipid peroxides (LPO) generated over 3 hours were measured. Patients were divided into 2 groups based on median serum PON1 activity. 2. 41 morbidly obese patients were divided into two groups based on the presence or absence of OSA ("OSA" and "no OSA" group) or on severity of OSA (high or low apnoea-hypoapnoea index (AHI) groups). I studied HDL's ability to protect itself from in vitro oxidation and measured serum PON1 activity, tumor necrosis factor alpha (TNFalpha) and intercellular adhesion molecule 1 (ICAM1). 3. This was a randomised double blind cross over trial, where I studied the effect of ERN/LRP compared to placebo in 27 patients who had high LDL-C inspite of maximum tolerated doses of statins. I measured lipid profile, apolipoproteins, cholesteryl ester transport protein (CETP) activity, paraoxonase 1 activity (PON1), oxidised LDL (oxLDL) and related mediators of vascular inflammation. I also examined the capacity of HDL to protect LDL from in vitro oxidation. Results and conclusion: 1. In statin treated dyslipidemic patients the capacity of HDL to protect itself and LDL from oxidation in vitro is significantly better in individuals with higher serum PON1 activity. 2. The capacity of HDL to protect itself from in vitro oxidation in morbidly obese patients is reduced with onset and severity of OSA. The differences in TNFalpha and ICAM1 levels may suggest endothelial dysfunction due to OSA. Oxidative damage of PON1 attributable to OSA could be a mechanism for HDL and endothelial dysfunction. 3. Treatment with ERN/LRP resulted in a significant improvement in HDL-C but did not affect HDL's in vitro anti-oxidant function in patients who had persistent dyslipidaemia despite high doses of potent statins. For the first time I have shown that ERN/LRP reduces mediators of vascular inflammation.

Submitted by Aline Batista (alinehb.ufpel@gmail.com) on 2018-05-18T21:39:46Z No. of bitstreams: 2 license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Dissertacao_Mauren_Ritta.pdf: 1714370 bytes, checksum: c3b75a7b6066c70fa02e7b57631677d6 (MD5) / Approved for entry into archive by Aline Batista (alinehb.ufpel@gmail.com) on 2018-05-18T22:43:18Z (GMT) No. of bitstreams: 2 license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Dissertacao_Mauren_Ritta.pdf: 1714370 bytes, checksum: c3b75a7b6066c70fa02e7b57631677d6 (MD5) / Approved for entry into archive by Aline Batista (alinehb.ufpel@gmail.com) on 2018-05-18T22:43:26Z (GMT) No. of bitstreams: 2 license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Dissertacao_Mauren_Ritta.pdf: 1714370 bytes, checksum: c3b75a7b6066c70fa02e7b57631677d6 (MD5) / Made available in DSpace on 2018-05-18T22:43:26Z (GMT). No. of bitstreams: 2 license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Dissertacao_Mauren_Ritta.pdf: 1714370 bytes, checksum: c3b75a7b6066c70fa02e7b57631677d6 (MD5) Previous issue date: 2017-08-04 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES / As doenças crônicas não transmissíveis (DCNT) representam a principal causa de morte no mundo. No Brasil, assim como em outros países, as doenças cardiovasculares (DCV’s) representam um terço dos óbitos em adultos. Em estudo que investigou a prevalência de DCV foi demonstrada que esta se apresentava igual entre os sexos quando as mulheres estavam no período pós-menopausa. A deficiência de estrógeno decorrente desse período está associada a alterações no perfil lipídico, distribuição e composição corporal, que levam a uma modificação oxidativa importante na etiologia da aterosclerose, pois a ação da lipoproteína de alta densidade (HDL-c) estará diminuída. A paraoxonase 1 (PON1) circula ligada ao HDL-c sendo a responsável pela ação ateroprotetora. O gene que codifica a PON1 tem diversos polimorfismos de nucleotídeo único (SNP do inglês, single nucleotide polymorphism), sendo aquele localizado na região promotora C(-107)T o que exerce efeito sobre a atividade sérica e expressão gênica. A atividade da PON1 sofre influencias genéticas, ambientais e fisiológicas que estimulam ou inibem sua ação e expressão. A dieta atua tanto na prevenção de DCV assim como na atividade da PON1. Diante deste contexto, em que diversos fatores contribuem para o risco de DCV’s e de poucos relatos científicos relacionando menopausa, dieta, genótipo e atividade da PON1, percebe-se a necessidade de ampliar os conhecimentos sobre a prevenção de comorbidades associadas a esta fase da vida da mulher. Este estudo foi proposto com o objetivo de relacionar o nível de atividade da PON1 no soro de mulheres em períodos pré e pós-menopausa com a presença do polimorfismo C(-107)T do gene da PON1 e consumo alimentar, visando identificar fatores de risco para DCV. Foi realizado um estudo transversal com 91 mulheres entre 20 e 59 anos, atendidas em serviço de nutrição, divididas em dois grupos, sendo 55 na pré-menopausa e 36 na pós-menopausa. Das participantes foram coletados dados antropométricos,amostra de sangue, aplicado questionário de frequência alimentar (QFA) e questionário geral sobre condições de saúde e hábitos de vida. Foi observada diferença significativa na população com o genótipo TT em relação à baixa atividade da PON1, predomínio de excesso de peso em ambos os grupos, perfil lipídico e glicêmico alterado com diferença significativa para o nível de colesterol total e glicemia de jejum, sendo evidenciada uma tendência ao aumento da lipoproteína de baixa densidade (LDL-c) e hemoglobina glicada (HbA1C) e diminuição no consumo de calorias e carboidratos nas pós-menopausa. A atividade da PON1 não apresentou interação com a menopausa, consumo de lipídios, alimentos processados e in natura. Concluindo estes resultados reforçam a importância de intervenções preventivas e promotoras de estilo de vida saudável, afim de contribuir para o controle de fatores de risco modificáveis, visto que população apresenta uma predisposição para o desenvolvimento de DCV. / Non-communicable chronic diseases (NCDs) are the leading cause of death in the world. In Brazil, as in other countries, cardiovascular diseases (CVDs) account for a third of deaths in adults. In a study investigating the prevalence of CVD, the same prevalence was found between sexes when the women were in the postmenopausal period. The estrogen deficiency during this period is associated with alterations in lipid profile, distribution of body fat and body composition. These changes lead to oxidative modifications, important in the etiology of atherosclerosis, since the action of high density lipoprotein (HDL-c) will be reduced. Paraoxonase 1 (PON1) circulates along HDL-c and is responsible for the atheroprotective action. The gene encoding PON1 has several single nucleotide polymorphisms (SNPs), and the one located in the C (-107) T promoter region has an effect on PON1 serum activity and gene expression. The activity of PON1 undergoes genetic, environmental and physiological influences that stimulate or inhibit its action and expression. The diet works both in the prevention of CVD as well as in the activity of PON1. In this context, several factors contribute to the risk of CVDs and there are few scientific reports associating menopause, diet, genotype and PON1 activity, it is necessary to increase the knowledge about the prevention of comorbidities associated with this stage of life of the woman. The aim of this study was to correlate the level of PON1 activity in the serum of pre and post menopausal women with the presence of the C (-107) T polymorphism of the PON1 gene and food consumption, aiming to identify risk factors for CVD. A cross-sectional study was carried out with 91 women between 20 and 59 years of age, that attended at a nutrition service, divided into two groups: 55 premenopausal women and 36 postmenopausal women. Anthropometric data was collected from the patients, as well as blood sample, a food frequency questionnaire (FFQ) and general questionnaire on health conditions and life habits were applied. A significant difference was observed in the population with the TT genotype, having lower PON1 activity, predominance of overweight in both groups, altered lipid and glycemic profile with significant difference for total cholesterol and fasting glycemia levels. A tendency to increase low-density lipoprotein (LDL-c) and glycated hemoglobin (HbA1C) and decrease post-menopausal calorie and carbohydrate intake was observed. The activity of PON1 did not show interaction with menopause, lipid consumption, and ingestion of processed foods or in natura. Concluding these results reinforce the importance of preventive and healthy lifestyle interventions in order to contribute to the control of modifiable risk factors, since the population presents a predisposition for the development of CVD.