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L'athérosclérose est la principale cause de mortalité dans les pays industrialisés. Les lipoprotéines de haute densité (HDL) ont pour rôle de contrebalancer les effets néfastes de part leurs propriétés antiathérogènes.L'effet bénéfique des HDL est dû à leur rôle dans le transport inverse du cholestérol (TIC), ainsi qu'à leurs activités antioxydante et anti-inflammatoire.L'efflux du cholestérol, une étape importante dans le TIC, peut être moduler par les différents processus du vieillissement. Le rôle de la PON1 dans l'activité antioxydante des HDL a été largement étudié, contrairement à l'implication de la PON1 dans l'activité anti-inflammatoire des HDL qui est moins bien établit. Une activité enzymatique de PON1, soit"phospholipase-A2 like" (PL-A2 like), est à l'origine d'une controverse sur le rôle de PON1 dans les processus anti-inflammatoires. D'autres parts, il est bien connu que le vieillissement constitue un facteur de risque important dans le processus d'athérosclérose et que ce phénomène se répercute sur plusieurs facteurs. Ainsi, nos principaux objectifs sont: (1) Déterminer l'impact du vieillissement sur la capacité des HDL à promouvoir le transport inverse du cholestérol (2) Déterminer le mécanisme d'action à l'origine de rôle athéro-protecteur de la PON1 et l'implication de son activité PL-A2 like dans les propriétés anti-inflammatoire des HDL. Nos résultats montrent une réduction dans la capacité des HDL à assurer l'efflux de cholestérol au cours du vieillissement (HDL-Jeune 49.0 « 2.2% vs. HDL-Âgé 41.7 « 1.4%, p=0.013). Cette diminution semble être attribuable aux modifications oxydatives qui semble intervenir au cours du vieillissement affectant l'intégrité d'apoA-I. Nos résultats montrent que la PON1 inhibe la formation de la Lyso-PC dans les HDL oxydées (HDL oxydées 8.25 « 0.54 [mu]g vs HDL oxydées + PON1 40 U/ml 3.68 « 1.32 [mu]g) mais contribue à la formation de Lyso-Pc dans les LDL oxydées (LDL oxydés 18.46 « 2.45 [mu]g vs LDL oxydés + PON1 40 U/ml 32.88 « 4.04 [mu]g).L'utilisation des HDL reconstituées a permis de mettre en évidence des interactions possibles entre PON1 avec la LCAT dans les HDL. En conclusions, nos résultats ont permis de démontré l'importance de l'intégrité d'apo-AI et du rôle de PON1 dans les activités anti-athérogènes des HDL.

L'incidence des maladies cardiovasculaires (MCV) dans la population âgée et particulièrement chez les femmes postménopausées en surpoids se montre sans cesse grandissante au fil des années. Cette augmentation de la survenue des MCV serait particulièrement due à une diminution d'oestrogène pendant la ménopause, à une redistribution de la masse grasse au niveau abdominal et à une augmentation de la production des radicaux libres au cours du vieillissement. Bien que les femmes postménopausées utilisent souvent des oestrogènes de synthèse pour soulager les symptômes de la ménopause, plusieurs études prospectives ont montré que la thérapie hormonale de substitution (THS) entraînait également une diminution significative des facteurs de risque des MCV et que des effets synergiques sur l'amélioration du profil lipidique étaient aussi observés lorsque la THS était associée à un programme d'exercices aérobies. Cependant, quelques études longitudinales récemment publiées ont montré que la THS entraînait non seulement une augmentation de l'incidence de cancers, mais aussi que celle-ci augmenterait la survenue d'attaques cardiaques et de maladies coronariennes. Les phytoestrogènes semblent être une alternative intéressante à la THS. En effet, plusieurs études longitudinales et in vitro ont montré que les phytoestrogènes diminuaient l'incidence des MCV en améliorant le profil lipidique et en augmentant la résistance des lipoprotéines de faible densité (LDL) à l'oxydation. Cet effet protecteur des phytoestrogènes à l'égard des LDL semble se faire par l'amélioration de l'activité de l'enzyme paraoxonase 1 (PON1) présente à la surface des lipoprotéines de haute densité (HDL). Ainsi, le but de notre étude est d'évaluer l'effet d'une supplémentation en phytoestrogènes associés à l'exercice physique sur les marqueurs du stress oxydatif et l'activité de la PON1 chez les femmes postménopausées présentant un gain pondéral. Pour ce faire, nous avons recruté des femmes âgées entre 50 et 75 ans que nous avons aléatoirement réparties en deux groupes, 25 femmes dans le groupes phytoestrogènes et 25 femmes dans le groupe placebo. Ces sujets devaient prendre des phytoestrogènes (70 mg/jour d'isoflavones) ou le placebo pendant une période de six mois, puis les deux groupes, en plus de ces suppléments, étaient soumis à des séances d'exercices aérobies pendant six mois additionnels. Des prélèvements sanguins étaient effectués au début de l'étude, après 6 mois et à la fin de la période de suivie (12 mois). Un certain nombre de marqueurs sanguins du stress oxydatif étaient mesurés, notamment l'activité antioxydante totale (AAOT) et résiduelle (AoGap), les diènes conjugués, les dialdéhydes maloniques (MDA), mais aussi la vitamine C, la vitamine E, l'activité paraoxonase et la leptine. Nos résultats montrent une augmentation significative de la vitamine C et de l'activité paraoxonase dans les deux groupes au bout des 12 mois de suivi et également une diminution significative de la vitamine E dans les deux groupes à l'issue de la même période. Aucune variation significative n'a été observée lors du dosage des autres variables. Ces résultats suggèrent que les phytoestrogènes n'ont aucun effet sur l'ensemble des marqueurs du stress oxydatif, mais que les variations significatives obtenues lors des dosages des vitamines C et E ainsi que de l'activité paraoxonase seraient dues à une réponse adaptative de l'organisme au stress induit par l'exercice physique. L'absence d'effets des phytoestrogènes pourrait aussi s'expliquer par le haut niveau d'abandons observé tout au long de l'étude ou encore par le fait que la dose prescrite n'est pas nécessairement suffisante pour avoir une influence positive sur les différentes variables étudiées.

Thesis (PhD)--Stellenbosch University, 2014. / ENGLISH ABSTRACT: Paraoxonase (PON) 1 is a high density lipoprotein (HDL) - bound antioxidant enzyme that was originally discovered and better known for its role in protecting against organophosphate (OP) - induced neurotoxicity. In the past two decades, the enzyme has gained prominence as a protective agent against atherosclerosis on account of increasing evidence that it accounts for many of the anti-atherogenic roles attributed to HDL. PON1 is a polymorphic enzyme displaying a high variability in human populations which is associated with a considerable degree of inter-individual differences in enzyme phenotype that translates to differential risk for OP toxicity and cardiovascular disease (CVD). In a series of studies and analyses, this thesis describes investigations regarding the possible involvement of PON 1 in the risk for CVD in a mixed ancestry population from Bellville, Western Cape, South Africa. This was done by evaluating the distribution of PON1 coding region polymorphisms (Q192R and L55M) and their influence on PON1 phenotype as well as the latter‟s relation to CVD risk factors (oxidative stress, inflammation and atherogenic dyslipidemia) and possible involvement in early CVD assessed by measuring intima media thickness of the carotid artery (CIMT). Since PON1 is increasingly measured in samples that have been stored for varied periods of time, the main study was preceded by a pilot study evaluating the influence of baseline conditions on the stability of PON 1 activity and antioxidant status in human sera stored for up to 12 months. It was shown that baseline glycemic status enhances the degradation of antioxidants in stored samples with indications of also accelerating the decline of PON1 levels and activity. Thus baseline glycemic status should be a factor to be considered in analyses involving stored samples. The Q192R polymorphism was found to be the functional variant influencing both concentration and activity of plasma PON1. Contrary to expectation, the L55M was nonfunctional, possibly due to its unusual distribution in this population where the 55M (83%) allele overwhelmingly predominated over the L55 allele. The R allele was the more frequent (60.4%) of the 192 polymorphism. The R allele has previously been associated with less efficient breakdown of lipid peroxides and a subsequent higher risk for atherosclerotic heart disease while the 55M is recognized as a “low concentration/activity” variant. Thus the predominant PON1 genotype distribution in this population constitutes a risk profile that may relate to increased risk for CVD. The risk for CVD was confirmed to be very high in this population indicated by high prevalence of the metabolic syndrome (48%) and its key components (and CVD risk factors) diabetes (28%), obesity (53%) and high blood pressure (57%). Paraoxonase activity associated inversely with indices of inflammation (high sensitive C- reactive protein [hs-CRP] and leptin) and oxidative stress (oxidized low density lipoprotein [LDL]) and directly with adiponectin and markers of systemic antioxidant status. These findings suggest that low paraoxonase-I activity contributes to increased cardiovascular risk possibly via involvement in early atherogenesis. However, only a modest inverse relation was observed between PON1 phenotype and CIMT thus suggesting that PON1 may not play a major role in early atherosclerosis. Taken together, the findings presented in this thesis demonstrate the presence of a risk PON1 genotypic profile and indication that the enzyme may play a role in the enhanced CVD risk in this population possibly via interactions with inflammation and oxidative stress. However, conclusive evidence for the involvement of PON1 in early CVD was not demonstrated indicating a need to explore the participation of PON1 in later stages of CVD. / AFRIKAANSE OPSOMMING: Paraoksonase (PON) 1 is 'n antioksidant ensiem wat aan HDL gebind is. Oorspronklik is dit ontdek en het bekend geword as 'n beskermer teen organofosfaat (OF)-gedrewe neurotoksisiteit. In die afgelope twee dekades het die ensiem belangrik geraak as 'n beskermer teen arterosklerose as gevolg van toenemende bewyse dat dit 'n belangrike rol speel in die beskermende effekte van HDL teen arterosklerose. PON1 is 'n polimorfiese ensiem wat groot variasie toon in verskillende populasies. Daar is ook inter-individuele verskille in ensiem fenotipe wat uitloop op 'n differensiele risiko vir OF toksisiteit en kardiovaskulêre hartsiekte (KVH). Hierdie tesis beskryf 'n reeks analises en ondersoeke betreffende die moontlike betrokkenheid van PON1 in die risiko vir KVH in 'n gemengdeafkoms populasie van Bellville, Wes-Kaap, Suid Afrika. Dit was gedoen deur die evaluering van die verspreiding van die PON-1 koderende omgewing polimorfismes (Q192R en L55M), hulle invloed op PON1 fenotipe en laasgenoemde se verhouding tot KVH risikofaktore (oksidatiewe stress, inflammasie en arterogeniese dislipedimie) en moontlike voorkoms in vroeë kardiovaskulêre siekte bepaal deur die meting van die intima media dikte van die karotied slagaar. Aangesien PON1 al hoe meer gemeet word in monsters wat vir verskeie tydperke gestoor word, was die hoofstudie voorafgegaan deur 'n loodsstudie wat die invloed van basislyn kondisies op die stabiliteit van PON1 aktiwiteit en antioksidant status in menslike sera wat vir tot 12 maande gestoor was, bepaal het. Dis is duidelik aangetoon dat basislyn glisemiese status die afbraak van antioksidante in gestoorde monsters verhoog het, asook aanduidings van die afname van PON1 vlakke en aktiwitetit. Basislyn glisemiese status behoort dus ook as 'n faktor ingereken te word in analises van gestoorde monsters. Die Q192R polimorfisme is aangetoon om 'n funksionele variant te wees wat beide die konsentrasie asook die aktiwiteit van PON1 beïnvloed het. Anders as wat verwag is, was die L55M polimorfisme nie-funksioneel, moontlik as gevolg van sy ongewone distribusie in hiedie populasie waar die voorkoms van die 55M (83%) alleel die L55 alleel oorheers het. Die R alleel was die mees algemene (60.4%) van die 192 polimorfisme. Die R alleel is voorheen reeds geassosieer met minder effektiewe afbraak van lipied peroksides en gevolglike hoër voorkoms van arteriosklerotiese hartsiekte, terwyl die 55M erken word as 'n “lae konsentrasie/aktiwiteit” variant. Die oorheersende PON1 genotipe distribusie in hierdie populasie behels dus 'n risikoprofiel wat betrekkking mag hê op verhoogde KVH. Die risiko vir KVH was bevestig om baie hoog te wees in hierdie populasie, soos aangedui deur 'n hoë voorkoms van die metaboliese sindroom (48%) en die sleutelkomponente daarvan (insluitend KVH risikofaktore), diabetes (28%), obesiteit (53%) en hipertensie (57%). Paraoksinase aktiwiteit was omgekeerd geassosieer met indekse van inflammasie (hoë C-reaktiewe proteïen [hs-CRP] en leptien) en oksidatiewe stres (geoksideerde lae digtheid lipoproteïen [LDL], en direk geassosieer met adiponektien en merkers van sistemiese antioksidantstatus. Hierdie bevindings mag aandui dat lae paraoksonase-1 aktiwiteit bydra tot verhoogde kardiovaskulêre risiko, moontlik via betrokkenheid in vroeë arterogenese. Slegs 'n klein omgekeerde verhouding is egter waargeneem tussen die PON1 fenotipe en karotied intima media dikte, wat mag aandui dat PON1 nie 'n beduidende rol speel in vroeë arterosklerose nie. In geheel, die bevindinge voorgedra in hierdie tesis demonstreer die voorkoms van 'n risiko PON1 genotipiese profiel wat 'n aanduiding mag wees dat die ensiem 'n rol mag speel in die verhoogde KVH risiko in hierdie populasie, moontlik deur interaksies met inflammasie en oksidatiewe stress. Afdoende bewys van die betrokkenheid van PON1 in vroeë KVH was egter nie gedemonstreer nie, wat die nodigheid aandui om die deelname van PON1 in latere stadiums van KVH te ondersoek.

No description available.

Título: Estresse oxidativo e hormônios esteróides na associação entre Distúrbios Respiratórios do Sono e Doença Aterosclerótica Coronariana Introdução: Estudos epidemiológicos mostram a existência de associação entre a Doença Aterosclerótica Coronariana (DAC) e os Distúrbios Respiratórios do Sono (DRS). Evidencias sugerem que o estresse oxidativo gerado pela hipóxia intermitente sofrida pelos pacientes com DRS pode estar relacionado à progressão da DAC. Os hormônios esteróides testosterona, progesterona e estradiol estão relacionados ao estresse oxidativo, e podem ter papel em ambas as doenças. A enzima glutationa S-tranferase utiliza a molécula antioxidante glutationa na detoxificação de compostos que podem ser formados neste processo. A enzima paraoxonase-1 hidrolisa peróxidos lipídicos, atuando sobre as lipoproteínas de baixa densidade oxidadas (ox-LDL). Ox-LDL são marcadores de peroxidação lipídica, e são importantes na formação da placa aterosclerótica. O vaso dilatador óxido nítrico (NO●) é considerado ateroprotetor e pode estar reduzido, agravando a DAC. Objetivos: Estudar o estresse oxidativo e as alterações fisiopatológicas decorrentes da associação entre DRS e DAC, e avaliar a participação dos hormônios esteroides neste processo. Material e Métodos: 56 pacientes com prévio diagnóstico para Doença Aterosclerótica Coronariana (DAC) e avaliação do Índice de Apneias-hipopneias (IAH) para diagnóstico de Distúrbio Respiratório do sono (DRS) foram divididos em dois grupos, 29 pacientes controles e 27 pacientes com DAC, definidos por apresentarem obstrução coronariana >30%. Foram quantificadas as concentrações séricas dos triglicerídeos, HDL, LDL, ferritina, tranferrina e ferro disponível, assim como dos níveis séricos dos hormônios testosterona, estradiol e progesterona, das enzimas paraoxonase-1 e glutationa S-transferase, e das ox-LDL. Foram quantificadas as concentrações de glutationa total, glutationa reduzida, glutationa oxidada e nitritos e nitratos (medida indireta de NO●) em eritrócitos. A concentração do marcador de dano oxidativo em DNA 8-oxo-7,8-dihidro-2’-desoxiguanosina foi obtida em leucócitos. Resultados: Pacientes com DAC possuem reduzida concentração de nitritos e nitratos. A concentração de 8-OHdG, a atividade da GsT, os níveis de glutationa total, glutationa reduzida e glutationa oxidada, assim com o estradiol e a progesterona, não apresentaram relação com DAC ou DRS. Além do IAH, a redução da testosterona e do ferro disponível estão relacionados a DAC. A redução da atividade da paraoxonase-1 e a maior concentração de ox-LDL são preditores de DAC. A testosterona está relacionada à concentração de ferritina, transferrina e ferro disponível nestes pacientes. A ferritina correlacionou-se positivamente ao dano oxidativo em proteínas e com o IAH, negativamente aos níveis de nitritos e nitratos, e é maior nos pacientes com DAC. Conclusão: Baixos níveis de testosterona e ferro disponível, assim com o aumento da ferritina podem estar relacionados à fisiopatologia da associação entre DRS e DAC. Paraoxonase-1 e ox-LDL são importantes preditores de DAC, mas parecem não estar diretamente relacionados ao IAH nestes pacientes. / Title: Oxidative stress and steroid hormones in the association between Sleep Disordered Breathing and Coronary Artery Disease Introduction: Epidemiological studies have shown a possible association between Coronary Artery Disease (CAD) and Sleep Disordered Breathing (SDB). Evidences suggest that oxidative stress generated by the intermittent hypoxia experienced by patients with sleep disorders may be related to progression of CAD. The steroid hormones testosterone, progesterone and estradiol are related to oxidative stress, and may have a role in both diseases. Glutathione S-transferase uses the antioxidant molecule glutathione in the detoxification of compounds that can be formed in this process. The enzyme paraoxonase-1 hydrolyzes lipid peroxides, acting on oxidized low-density lipoproteins (ox-LDL). Ox-LDL are lipid peroxidation markers, being important for the atherosclerotic plaque formation. The vasodilator nitric oxide (NO●) is considered atheroprotective and can be reduced, aggravating DAC. Objective: Evaluate the oxidative stress and the pathophysiological changes arising from the association between SDB and CAD, and the role of steroid hormones in this process. Material and Methods: 56 patients with prior Coronary Artery Disease (CAD) diagnosis and apnea-hypopnea index (AHI) evaluation for diagnosis of sleep-disordered breathing (SDB) were divided into two groups, 29 control patients and 27 patients with CAD, defined by present a coronary obstruction > 30%. The serum concentration of triglycerides, HDL, LDL, ferritin, transferrin and available iron was obtained, as well as the serum levels of the hormones testosterone, estradiol and progesterone, enzymes paraoxonase-1 and glutathione S-transferase, and ox-LDL. Were measured concentrations of total glutathione, reduced glutathione, glutathione disulfide and nitrites and nitrates (NO● indirect measure) in erythrocytes. The concentration of the 8-oxo-7,8-dihydro-2'-deoxyguanosine, oxidative DNA damage marker, was obtained from leukocytes. Results: CAD patients have reduced concentrations of nitrates and nitrites. The concentration of 8-OHdG, GST activity, levels of total glutathione, reduced glutathione and glutathione disulfide, and estradiol and progesterone, showed no relationship with CAD or SDB. In addition to AHI, the reduction of testosterone and iron available are related to CAD. The reduced activity of paraoxonase-1 and the highest concentration of ox-LDL are CAD predictors. Testosterone is related to the concentration of ferritin, transferrin and iron available in these patients. Ferritin was positively correlated to oxidative damage in protein and with the AHI, and negatively to the levels of nitrites and nitrates, and is higher in CAD patients. Conclusion: Low testosterone levels and iron available, as well as the increase ferritin may be related to the pathophysiology of the association between SDB and CAD. Paraoxonase-1 and ox-LDL are important CAD predictors, but do not seem to be directly related to AHI in these patients.

Título: Estresse oxidativo e hormônios esteróides na associação entre Distúrbios Respiratórios do Sono e Doença Aterosclerótica Coronariana Introdução: Estudos epidemiológicos mostram a existência de associação entre a Doença Aterosclerótica Coronariana (DAC) e os Distúrbios Respiratórios do Sono (DRS). Evidencias sugerem que o estresse oxidativo gerado pela hipóxia intermitente sofrida pelos pacientes com DRS pode estar relacionado à progressão da DAC. Os hormônios esteróides testosterona, progesterona e estradiol estão relacionados ao estresse oxidativo, e podem ter papel em ambas as doenças. A enzima glutationa S-tranferase utiliza a molécula antioxidante glutationa na detoxificação de compostos que podem ser formados neste processo. A enzima paraoxonase-1 hidrolisa peróxidos lipídicos, atuando sobre as lipoproteínas de baixa densidade oxidadas (ox-LDL). Ox-LDL são marcadores de peroxidação lipídica, e são importantes na formação da placa aterosclerótica. O vaso dilatador óxido nítrico (NO●) é considerado ateroprotetor e pode estar reduzido, agravando a DAC. Objetivos: Estudar o estresse oxidativo e as alterações fisiopatológicas decorrentes da associação entre DRS e DAC, e avaliar a participação dos hormônios esteroides neste processo. Material e Métodos: 56 pacientes com prévio diagnóstico para Doença Aterosclerótica Coronariana (DAC) e avaliação do Índice de Apneias-hipopneias (IAH) para diagnóstico de Distúrbio Respiratório do sono (DRS) foram divididos em dois grupos, 29 pacientes controles e 27 pacientes com DAC, definidos por apresentarem obstrução coronariana >30%. Foram quantificadas as concentrações séricas dos triglicerídeos, HDL, LDL, ferritina, tranferrina e ferro disponível, assim como dos níveis séricos dos hormônios testosterona, estradiol e progesterona, das enzimas paraoxonase-1 e glutationa S-transferase, e das ox-LDL. Foram quantificadas as concentrações de glutationa total, glutationa reduzida, glutationa oxidada e nitritos e nitratos (medida indireta de NO●) em eritrócitos. A concentração do marcador de dano oxidativo em DNA 8-oxo-7,8-dihidro-2’-desoxiguanosina foi obtida em leucócitos. Resultados: Pacientes com DAC possuem reduzida concentração de nitritos e nitratos. A concentração de 8-OHdG, a atividade da GsT, os níveis de glutationa total, glutationa reduzida e glutationa oxidada, assim com o estradiol e a progesterona, não apresentaram relação com DAC ou DRS. Além do IAH, a redução da testosterona e do ferro disponível estão relacionados a DAC. A redução da atividade da paraoxonase-1 e a maior concentração de ox-LDL são preditores de DAC. A testosterona está relacionada à concentração de ferritina, transferrina e ferro disponível nestes pacientes. A ferritina correlacionou-se positivamente ao dano oxidativo em proteínas e com o IAH, negativamente aos níveis de nitritos e nitratos, e é maior nos pacientes com DAC. Conclusão: Baixos níveis de testosterona e ferro disponível, assim com o aumento da ferritina podem estar relacionados à fisiopatologia da associação entre DRS e DAC. Paraoxonase-1 e ox-LDL são importantes preditores de DAC, mas parecem não estar diretamente relacionados ao IAH nestes pacientes. / Title: Oxidative stress and steroid hormones in the association between Sleep Disordered Breathing and Coronary Artery Disease Introduction: Epidemiological studies have shown a possible association between Coronary Artery Disease (CAD) and Sleep Disordered Breathing (SDB). Evidences suggest that oxidative stress generated by the intermittent hypoxia experienced by patients with sleep disorders may be related to progression of CAD. The steroid hormones testosterone, progesterone and estradiol are related to oxidative stress, and may have a role in both diseases. Glutathione S-transferase uses the antioxidant molecule glutathione in the detoxification of compounds that can be formed in this process. The enzyme paraoxonase-1 hydrolyzes lipid peroxides, acting on oxidized low-density lipoproteins (ox-LDL). Ox-LDL are lipid peroxidation markers, being important for the atherosclerotic plaque formation. The vasodilator nitric oxide (NO●) is considered atheroprotective and can be reduced, aggravating DAC. Objective: Evaluate the oxidative stress and the pathophysiological changes arising from the association between SDB and CAD, and the role of steroid hormones in this process. Material and Methods: 56 patients with prior Coronary Artery Disease (CAD) diagnosis and apnea-hypopnea index (AHI) evaluation for diagnosis of sleep-disordered breathing (SDB) were divided into two groups, 29 control patients and 27 patients with CAD, defined by present a coronary obstruction > 30%. The serum concentration of triglycerides, HDL, LDL, ferritin, transferrin and available iron was obtained, as well as the serum levels of the hormones testosterone, estradiol and progesterone, enzymes paraoxonase-1 and glutathione S-transferase, and ox-LDL. Were measured concentrations of total glutathione, reduced glutathione, glutathione disulfide and nitrites and nitrates (NO● indirect measure) in erythrocytes. The concentration of the 8-oxo-7,8-dihydro-2'-deoxyguanosine, oxidative DNA damage marker, was obtained from leukocytes. Results: CAD patients have reduced concentrations of nitrates and nitrites. The concentration of 8-OHdG, GST activity, levels of total glutathione, reduced glutathione and glutathione disulfide, and estradiol and progesterone, showed no relationship with CAD or SDB. In addition to AHI, the reduction of testosterone and iron available are related to CAD. The reduced activity of paraoxonase-1 and the highest concentration of ox-LDL are CAD predictors. Testosterone is related to the concentration of ferritin, transferrin and iron available in these patients. Ferritin was positively correlated to oxidative damage in protein and with the AHI, and negatively to the levels of nitrites and nitrates, and is higher in CAD patients. Conclusion: Low testosterone levels and iron available, as well as the increase ferritin may be related to the pathophysiology of the association between SDB and CAD. Paraoxonase-1 and ox-LDL are important CAD predictors, but do not seem to be directly related to AHI in these patients.

Título: Estresse oxidativo e hormônios esteróides na associação entre Distúrbios Respiratórios do Sono e Doença Aterosclerótica Coronariana Introdução: Estudos epidemiológicos mostram a existência de associação entre a Doença Aterosclerótica Coronariana (DAC) e os Distúrbios Respiratórios do Sono (DRS). Evidencias sugerem que o estresse oxidativo gerado pela hipóxia intermitente sofrida pelos pacientes com DRS pode estar relacionado à progressão da DAC. Os hormônios esteróides testosterona, progesterona e estradiol estão relacionados ao estresse oxidativo, e podem ter papel em ambas as doenças. A enzima glutationa S-tranferase utiliza a molécula antioxidante glutationa na detoxificação de compostos que podem ser formados neste processo. A enzima paraoxonase-1 hidrolisa peróxidos lipídicos, atuando sobre as lipoproteínas de baixa densidade oxidadas (ox-LDL). Ox-LDL são marcadores de peroxidação lipídica, e são importantes na formação da placa aterosclerótica. O vaso dilatador óxido nítrico (NO●) é considerado ateroprotetor e pode estar reduzido, agravando a DAC. Objetivos: Estudar o estresse oxidativo e as alterações fisiopatológicas decorrentes da associação entre DRS e DAC, e avaliar a participação dos hormônios esteroides neste processo. Material e Métodos: 56 pacientes com prévio diagnóstico para Doença Aterosclerótica Coronariana (DAC) e avaliação do Índice de Apneias-hipopneias (IAH) para diagnóstico de Distúrbio Respiratório do sono (DRS) foram divididos em dois grupos, 29 pacientes controles e 27 pacientes com DAC, definidos por apresentarem obstrução coronariana >30%. Foram quantificadas as concentrações séricas dos triglicerídeos, HDL, LDL, ferritina, tranferrina e ferro disponível, assim como dos níveis séricos dos hormônios testosterona, estradiol e progesterona, das enzimas paraoxonase-1 e glutationa S-transferase, e das ox-LDL. Foram quantificadas as concentrações de glutationa total, glutationa reduzida, glutationa oxidada e nitritos e nitratos (medida indireta de NO●) em eritrócitos. A concentração do marcador de dano oxidativo em DNA 8-oxo-7,8-dihidro-2’-desoxiguanosina foi obtida em leucócitos. Resultados: Pacientes com DAC possuem reduzida concentração de nitritos e nitratos. A concentração de 8-OHdG, a atividade da GsT, os níveis de glutationa total, glutationa reduzida e glutationa oxidada, assim com o estradiol e a progesterona, não apresentaram relação com DAC ou DRS. Além do IAH, a redução da testosterona e do ferro disponível estão relacionados a DAC. A redução da atividade da paraoxonase-1 e a maior concentração de ox-LDL são preditores de DAC. A testosterona está relacionada à concentração de ferritina, transferrina e ferro disponível nestes pacientes. A ferritina correlacionou-se positivamente ao dano oxidativo em proteínas e com o IAH, negativamente aos níveis de nitritos e nitratos, e é maior nos pacientes com DAC. Conclusão: Baixos níveis de testosterona e ferro disponível, assim com o aumento da ferritina podem estar relacionados à fisiopatologia da associação entre DRS e DAC. Paraoxonase-1 e ox-LDL são importantes preditores de DAC, mas parecem não estar diretamente relacionados ao IAH nestes pacientes. / Title: Oxidative stress and steroid hormones in the association between Sleep Disordered Breathing and Coronary Artery Disease Introduction: Epidemiological studies have shown a possible association between Coronary Artery Disease (CAD) and Sleep Disordered Breathing (SDB). Evidences suggest that oxidative stress generated by the intermittent hypoxia experienced by patients with sleep disorders may be related to progression of CAD. The steroid hormones testosterone, progesterone and estradiol are related to oxidative stress, and may have a role in both diseases. Glutathione S-transferase uses the antioxidant molecule glutathione in the detoxification of compounds that can be formed in this process. The enzyme paraoxonase-1 hydrolyzes lipid peroxides, acting on oxidized low-density lipoproteins (ox-LDL). Ox-LDL are lipid peroxidation markers, being important for the atherosclerotic plaque formation. The vasodilator nitric oxide (NO●) is considered atheroprotective and can be reduced, aggravating DAC. Objective: Evaluate the oxidative stress and the pathophysiological changes arising from the association between SDB and CAD, and the role of steroid hormones in this process. Material and Methods: 56 patients with prior Coronary Artery Disease (CAD) diagnosis and apnea-hypopnea index (AHI) evaluation for diagnosis of sleep-disordered breathing (SDB) were divided into two groups, 29 control patients and 27 patients with CAD, defined by present a coronary obstruction > 30%. The serum concentration of triglycerides, HDL, LDL, ferritin, transferrin and available iron was obtained, as well as the serum levels of the hormones testosterone, estradiol and progesterone, enzymes paraoxonase-1 and glutathione S-transferase, and ox-LDL. Were measured concentrations of total glutathione, reduced glutathione, glutathione disulfide and nitrites and nitrates (NO● indirect measure) in erythrocytes. The concentration of the 8-oxo-7,8-dihydro-2'-deoxyguanosine, oxidative DNA damage marker, was obtained from leukocytes. Results: CAD patients have reduced concentrations of nitrates and nitrites. The concentration of 8-OHdG, GST activity, levels of total glutathione, reduced glutathione and glutathione disulfide, and estradiol and progesterone, showed no relationship with CAD or SDB. In addition to AHI, the reduction of testosterone and iron available are related to CAD. The reduced activity of paraoxonase-1 and the highest concentration of ox-LDL are CAD predictors. Testosterone is related to the concentration of ferritin, transferrin and iron available in these patients. Ferritin was positively correlated to oxidative damage in protein and with the AHI, and negatively to the levels of nitrites and nitrates, and is higher in CAD patients. Conclusion: Low testosterone levels and iron available, as well as the increase ferritin may be related to the pathophysiology of the association between SDB and CAD. Paraoxonase-1 and ox-LDL are important CAD predictors, but do not seem to be directly related to AHI in these patients.

Abstract Atherosclerosis is a multifactorial disease with numerous genes and environmental factors affecting its intiation and progression. During the past years many candidate genes for atherosclerosis have been suggested, and it has also become evident that the immune system plays a part in atherogenesis. Early atherosclerotic changes can be effectively detected by measuring carotid artery intima-media thickness (IMT). In the present study the associations between IMT and polymorphisms of three candidate genes for atherosclerosis were studied: endothelial nitric oxide synthase (eNOS), apolipoprotein E (apoE) and paraoxonase-1 (PON1). To assess the role of immunological factors determining carotid atherosclerosis, CRP and circulating autoantibodies to oxidised LDL were studied in relation to IMT. The study population consisted of 519 hypertensive and 526 control subjects from a middle-aged population in Oulu, Finland. The results showed that the investigated polymorphisms of eNOS and PON1 genes were not associated with IMT, suggesting that these polymorphisms are not major risk factors for atherosclerosis in the general Caucasian population. A significant interaction between the apoE polymorphism and smoking in relation to IMT was observed among men, indicating that carriers of the ε4 allele may be particularly prone to the atherogenic effects of smoking. This interaction was especially clear in hypertensive subjects. CRP was strongly associated with IMT before adjusting for confounding factors. After the adjustment, this association diasppeared. The finding suggests that instead of early atherosclerosis CRP may be related to the later phases of the disease. This may partly explain the strong correlation between CRP and future cardiovascular events. IgM type of autoantibodies binding to oxidised LDL were inversely associated with IMT, and this finding remained after adjusting for previously known risk factors for atherosclerosis, implying a possible protective role for these antibodies in atherogenesis.

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