Many HIV-positive (HIV+) males on Highly Active Anti-Retroviral Therapy (HAART) experience metabolic abnormalities, including Non-Alcoholic Fatty Liver Disease (NAFLD) and lipodystrophy. The intestinal microbiota and short chain fatty acids (SCFA), participate in bidirectional communication with their host. Dysbiosis in HIV+ males on HAART demonstrate a Prevotella-rich enterotype shaped by multiple factors including, medications, adiposity, diet, intestinal permeability, and lifestyle; our objective was to investigate these factors. 19 HIV+ and 21 HIV- males were enrolled. BMI and hip-to-waist ratio (H:W) were obtained, and FibroScan for liver health. Intestinal permeability markers Claudin-21, flagellin, and intestinal fatty acid binding protein (IFABP) in serum via enzyme-linked immunoassay (ELISA). Stool was collected for 16s rRNA sequencing, SCFAs (gas chromatography), and proximate analyses (PA). PA analyses: Bomb calorimetry (kcal), soxhlet for lipids, kjeldhal for protein, and fiber. Dietary intake by food frequency questionnaires (FFQ). HIV+ males had significantly higher H:W and hepatic steatosis (pPrevotella and Lachnospiraceae compared to HIV- males. Additionally, HIV+ males had significantly higher central obesity and hepatic steatosis. In a retrospective analysis, all HIV+ men were men that have sex with men (MSM). These findings support differences in intestinal microbiome and SCFAs, and measures of altered lipid metabolism between HIV+ and HIV- males. These findings lay the framework for investigations into intestinal microbiome, SCFAs and metabolism in HIV+ MSM.

<p dir="ltr">Membrane-dependent enzymes play crucial roles in cellular signaling by transducing extracellular signals into intracellular responses. Phospholipase Cepsilon (PLCe) and diacylglycerol kinase alpha (DGKa) are membrane-associated enzymes regulated by G protein-coupled receptors (GPCRs) and receptor tyrosine kinases (RTKs), controlling signaling pathways essential for numerous cellular processes. PLCe catalyzes the hydrolysis of phosphatidylinositol phosphates into inositol phosphates (IPX) and diacylglycerol (DAG), triggering calcium release from intracellular stores and activating protein kinase C (PKC)-dependent pathways. While PLCe is crucial for normal cardiovascular function, hyperactivation or sustained activation can lead to hypertrophy. Due to structural heterogeneity, previous studies focused on isolated regulatory domains or the catalytic core. In this work, I present the first cryo-EM reconstruction of the largest PLCe fragment to date in complex with an antigen-binding fragment (Fab). This structure reveals the domain architecture of the N-terminal regions of the lipase and defines an extended membrane-binding surface critical for maximal basal and G protein-dependent activity. These findings lay the groundwork for high-resolution structures of the full-length enzyme and its complexes with the small GTPase Rap1A. Additionally, I explored the role of mAKAP in the Rap1A–PLCe pathway, alongside the guanine nucleotide exchange factor (GEF) function of PLCe toward Rap1A. In parallel, cryo-EM studies of DGKa bound to a covalent inhibitor were initiated. DGKa reduces DAG, thereby limiting PKC activity, and its inhibition is emerging as a promising cancer immunotherapy target. We have established a protocol for structural studies of full-length DGKa, which will elucidate its structures in basal and inhibited states.</p>

<p dir="ltr">Fibromuscular Dysplasia (FMD) is a non-inflammatory, non-atherosclerotic blood vessel disorder characterized by a series of narrowed and dilated regions of vasculature. These patients are prescribed blood thinners or anti-platelet therapeutics as treatment to this systemic disease. Current image-based diagnostic methods cannot reliably predict a patient’s risk of stroke in order to properly manage medication. There are also challenges in distinguishing FMD from other diseases that can cause arterial obstructions, like atherosclerosis or vasculitis.</p><p dir="ltr">The ultimate goal of this research is to develop a methodology for evaluating the risk of mechanical platelet activation based on medical imaging. Our hypothesis is that subject-specific assessment of platelet activation due to hemodynamic stress can improve risk stratification of FMD patients. The aims of the projects were therefore to 1) Develop a CFD-based methodology for estimating platelet activation state, and 2) Test this methodology on a small cohort of subjects with FMD, carotid artery stenosis, and healthy controls. A modeling workflow was developed, combining Eulerian and Lagrangian approaches to compute flow fields and evaluate shear stress history of particles advected through the vascular geometries. From this stress history, predictive estimates of mechanical platelet activation can be calculated utilizing a platelet activation state (PAS) metric. We applied this modeling workflow to assess platelet activation in segments of carotid arteries of patients with Fibromuscular Dysplasia, Carotid Artery Stenosis, and healthy controls for comparison against experiments performed at the Cleveland Clinic assessing mechanical platelet activation in patients with each of these conditions. This work supports the development of a patient-specific determination of these same metrics, in order to more precisely assess patient risk of stroke.</p>

In conclusion, the current air pollution levels in Hong Kong had a risk for school children's respiratory and cardiovascular health. In comparison between the highly- and least-polluted districts, a rise of 8 mug/m 3 annual mean for PM10 concentration was significantly associated with increased risks for some respiratory symptoms such as wheezing, cough, and phlegm, with decreased lung function in FEF25-75% and FEF75%, and with decreased cardiopulmonary fitness in predicted VO2max, after adjustment for confounding factors. An increase of 13 mug/m3 annual mean for NO2 in the moderately-polluted district did not individually cause adverse effects on children's respiratory and cardiopulmonary health. Physical activity appears to have no positive health effects on the children's VO2max in moderately- and highly-polluted districts. / In the past year preceding the study (May 2003 to April 2004), the annual means for PM10, NO2, SO2 and O3 were respectively 55.1 mug/m3, 51.4 mug/m3, 15.4 mug/m3, and 42.5 mug/m3 in the least-polluted district (LPD); 56.3 mug/m3, 64.7 mug/m3, 15.2 mug/m3, and 35.2 mug/m3 in the moderately-polluted district (MPD); and 63.8 mug/m3, 64.1 mug/m3, 22.2 mug/m3, and 31.7 mug/m3 in the highly-polluted district (HPD). The 99th percentiles were 178 mug/m3, 158 mug/m 3, 104 mug/m3, and 140 mug/m3 in the LPD; 169 mug/m3, 181 mug/m3, 106 mug/m 3, and 113 mug/m3 in the MPD; and 226 mug/m 3, 177 mug/m3, 140 mug/m3, and 137 mug/m 3 in the HPD. The average daily 1-h maximum O3 (peak O 3) was 83.7 mug/m3 in the LPD, 73.6 mug/m 3 in the MPD, and 64.8 mug/m3 in the HPD. / Lung function indices included FVC, FEV1, FEV 1/FVC, FEF25-75%, FEF25%, and FEF75%. Children in the HPD had lower FEV 1/FVC, FEF25-75%, and FEF25% than those in both the LPD and MPD, after controlling for their corresponding confounders. In comparison between the LPD and HPD, the adjusted mean differences for FEV1/FVC, FEF25-75%, and FEF25% were respectively 1.39%, 85 ml, and 113 ml in boys, and 1.60%, 86 ml, and 225 ml in girls. In addition, the decreased FEF75% of HPD was found in boys (62 ml) but not in girls. When comparing the MPD with LPD, the increased FEF25% was observed in girls in the LPD (158 ml), whereas boys in the LPD had lower FEF75% than those in the MPD (81 ml). There were no significant differences in children's FVC and FEV1 between districts. / The multistage fitness test (MFT) with the Matsuzaka's function was employed to predict cardiopulmonary fitness (VO2max) of children. After adjustment for the factors, girls in the LPD had significantly higher VO 2max than those in the MPD and HPD by 0.19 and 0.75 ml&middot;kg -1 &middot;min-1 respectively. The VO 2max among boys in the LPD was 0.48 ml&middot;kg-1 &middot;min -1 higher than those in the HPD. When we compared the VO 2max between students in MPD and HPD, higher VO2max in both boys and girls in the MPD were observed---by 0.49 and 0.56 ml&middot;kg -1 &middot;min-1 respectively. In LPD, significantly higher VO2max values were observed in both boys and girls who were physically active (children who took part in sports and/or vigorous free play at least three times a week for at least 30 minutes each time) compared with those who were not (0.71 and 0.65 ml&middot;kg-1 &middot;min -1 respectively), but those differences in VO2max among students in MPD and HPD were small and insignificant. / There were totally 2,641 (82.9%) children who participated in the study, and 2,203 participants were involved in analyses. After adjustment for confounding factors, girls living in the HPD had significantly increased odds ratios (ORs) for wheezing without cold (4.75), cough at night (1.71), phlegm without cold (3.61), compared with those in the LPD. Boys in the HPD had increased OR only for phlegm without cold (1.88). When comparing the MPD with LPD, the adjusted OR for cough at night achieved significance in girls (1.74) and marginal significance in boys (1.40). Sneeze with itchy-watery eyes and current/ever allergic rhinitis had negative associations with district. In comparison with LPD, the decreased OR for sneeze with itchy-watery eye in girls in HPD (0.65) reached statistical significance. Both boys and girls in MPD had significantly decreased ORs for current allergic rhinitis (0.72 and 0.50 respectively) and for ever allergic rhinitis (0.74 and 0.55 respectively). There were no significant differences in the prevalence rates of asthma and bronchitis between districts. / To explore associations between air pollution and respiratory and cardiovascular health of school children, a cross-sectional study was conducted among 3,186 primary school children in P3 and P4 from three districts with different air pollution levels in Hong Kong during March to June in 2004. / Gao Yang. / "August 2005." / Source: Dissertation Abstracts International, Volume: 67-11, Section: B, page: 6339. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2005. / Includes bibliographical references (p. 137-154). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstracts in English and Chinese. / School code: 1307.

Cardiovascular disease (CVD) is the leading cause of death worldwide and is partially attributed to perturbations in lipid metabolism. Xenobiotics, such as pharmaceutical drugs and environmental chemicals, have been associated with increased risk of CVD in multiple large-scale human population studies, but the underlying mechanisms remain poorly defined. We and others have identified several xenobiotics as potent agonists for the pregnane X receptor (PXR), a nuclear receptor that can be activated by numerous drugs as well as environmental and dietary chemicals. However, the role of PXR in mediating the pathophysiological effects of xenobiotic exposure in humans and animals remains elusive. The work herein identified several widely used pharmaceutical agents and endocrine disrupting chemicals as PXR-selective agonists such as drugs involved in HIV therapy and phthalates/phthalate substitutes, respectively. We investigated the role of amprenavir, an HIV protease inhibitor, and tributyl citrate, a phthalate substitute, on PXR-dependent alterations in lipoprotein metabolism. Acute exposure with either xenobiotic in mice elicited increases in the proatherogenic LDL-cholesterol levels in a PXR-dependent manner. PXR activation significantly induced expression of genes involved in intestinal lipid metabolism. Further, we went on to identify the intestinal cholesterol transporter, Niemann-Pick C1-Like 1 (NPC1L1), as a direct PXR-target gene. PXR activation also stimulated cholesterol uptake in both murine and human intestinal cells. Moreover, we provide evidence that the microsomal triglyceride transfer protein (MTP) may be a direct PXR-target gene. Taken together, these findings provide critical mechanistic insight into the role of xenobiotic-mediated PXR activation on lipid homeostasis and demonstrate a potential role of PXR in mediating adverse effects of xenobiotics on CVD risk in humans. In addition to PXR signaling, we investigated the role of IκB kinase β (IKKβ), a central coordinator of inflammation, in adipocyte progenitor cells. Targeting IKKβ in adipose progenitor cells resulted in decreased high fat diet (HFD)-elicited adipogenesis, while protecting mice from inflammation and associated insulin resistance. Consistently, we discovered that IKKβ inhibition by antisense oligonucleotides ablated HFD-induced adiposity, while protecting mice against associated metabolic disorders. In conclusion, targeting IKKβ with antisense therapy may present as a novel therapeutic approach to combat obesity and metabolic dysfunctions.

Syfte och frågeställningar Syftet med den här studien har varit att undersöka och jämföra kvinnor och män i åldersgrupperna 30-39 år respektive 40-49 år avseende antropometriska mått samt prestation på GIH:s hälsotester. En vidare målsättning var att undersöka om det förekom några skillnader mellan två separata testtillfällen. Frågeställningarna har varit om resultaten på hälsotesterna skiljer sig mellan könen, åldersgrupperna samt mellan två separata testtillfällen. Metod Totalt fullföljde 41 deltagare GIH:s hälsotester, av dem var 20 kvinnor och 21 män mellan 30-49 år. Det enda som krävdes för att delta var att man uppfattade sig själv som frisk. Personer som tidigare haft stroke, hjärtinfarkt eller opererats på grund av hjärtproblem har inte inkluderats, ej heller gravida och personer med ledbesvär. Testerna utfördes på LTIV (Laboratoriet för tillämpad idrottsvetenskap) mellan februari och mars 2016. Resultat Signifikanta skillnader mellan de två separata testtillfällena noterades för några av styrketesterna framför allt hos männen: axelpressar, handgrip och stolresningar. Mellan könen sågs signifikanta skillnader i de antropometriska måtten, samt i flera konditions- och styrketester. Bland dessa kunde signifikant högre värden ses för kvinnorna än för männen i ryggstyrketestet.  Signifikanta skillnader mellan åldersgrupperna 30-39 år och 40-49 år sågs näst intill endast för kvinnor. De yngre jämfört med de äldre kvinnorna presterade bättre i flera av testerna, de vägde mindre och hade mindre kroppsmått. Slutsats Det framkom vanligtvis inte några signifikanta skillnader mellan det första och andra testtillfället, med enstaka undantag. När så är fallet behövs bara ett test utföras initialt inför en period med exempelvis fysisk aktivitet som senare kanske ska följas upp med ett återtest. Skillnader mellan könen och olika åldersgrupper framkom i vissa tester men inte i alla. Resultaten i denna studie beror bland annat på urvalet av individer. Eftersom att syftet med den här studien har varit att endast utföra de tester som ingår i GIH:s hälsotester har inga tester lagts till eller exkluderats. I arbetet diskuteras bland annat hur optimala testerna är som ett mått på hälsa. För att effektivisera hälsotestundersökningar framöver behöver nödvändigtvis inte alla tester utföras.

Il presente lavoro di tesi è stato condotto in ambito psicocardiologico, e riguarda l’indagine delle determinanti psicosociali potenzialmente coinvolte nell’eziopatogenesi, digressione e prognosi delle malattie cardiache. Più studi preliminari sono stati condotti a fini esplorativi, e solo le varabili risultate caratteristiche del campione mantenute in indagini successive. Dopo aver indagato il ruolo del benessere psicologico nell’influenzare la Capacità Funzionale dei pazienti, uno degli indicatori di esito di maggiore importanza in Riabilitazione Cardiologica (RC) (studio 1), si è proceduto a verificare quali tra le variabili cognitive e psicologiche tradizionalmente associate alle malattie cardiache caratterizzasse lo specifico campione, condizionandone Qualità della Vita (QdV) e benessere psicologico (studio 2). Esclusa l’influenza delle variabili cognitive sullo stato emotivo dei soggetti, si è, poi, approfondito il ruolo delle variabili psicologiche nel determinarne la QdV percepita dei degenti (studio 3). Obiettivo del quarto studio è, infine, valutare efficacia ed efficienza dell’aggiunta di tecniche e principi propri del Colloquio Motivazionale (CM) al trattamento psicologico standard (Terapia Breve Strategica, TBS), al di la del solo trattamento breve strategico, nell’incrementare autoefficacia percepita, disponibilità al cambiamento ed aderenza al trattamento riabilitativo nel malati di cuore. Un esempio dell’uso di tale stile comunicativo viene, inoltre, proposto mediante caso clinico (studio 5). / The general aim of this thesis is to seek evidence on how to achieve long-term maintenance of lifestyle changes in a sample of obese inpatients with heart diseases referred to Cardiac Rehabilitation by investigating the influence of selected variables on their physical and psychological status, as well as by examining the efficacy and effectiveness of a motivational-based intervention. Study 1 is aimed at evaluating whether psychological well-being represents an independent predictor of Exercise Capacity. Study 2 focuses on investigating the influence of cognitive abilities and established psychosocial risk factors on the sample’s subjective Quality of life (QoL) and well-being. Since no effect of different levels of cognitive impairments on the expression of psychological distress among the study participants has been identified, in study 3 the effect of emotional impairments on QoL has been further explored. To conclude, the MOTIV-HEART study (study 4) is aimed at testing the incremental efficacy of a brief strategic treatment including motivational components (BST + MI) in improving physical and psychological outcomes over and beyond the stand-alone brief strategic treatment (BST) and whether results will be maintained/increased at 3-month follow-up. An example of this style of communication is also presented through a case study (study 5).

Les maladies cardiovasculaires sont la principale cause de mortalité dans les pays occidentaux et représentent une complication majeure du syndrome métabolique. Il est maintenant largement admis que l’athérosclérose est une maladie inflammatoire chronique et que l’inflammation joue un rôle pathogénique majeur dans l’initiation et la progression de la maladie athéromateuse. Il a été démontré qu’une augmentation des niveaux sériques de la protéine c-réactive (CRP), une protéine de la phase aigüe et un important constituant de la réponse immunitaire de type inné, est associée à un risque cardiovasculaire accru. Ainsi, il a été documenté qu’une augmentation de CRP, tant chez les sujets sains que chez les sujets diabétiques, était associée à une augmentation du risque de morbidité et de mortalité cardiovasculaires. De multiples évidences suggèrent que la CRP puisse non seulement constituer un marqueur de risque des maladies cardiovasculaires mais aussi représenter un facteur pro-athérogénique direct. La dysfonction endothéliale représente un des stades les plus précoces du processus athérosclérotique et un rôle de la CRP dans la pathogenèse de la dysfonction endothéliale est postulé. Outre son origine systémique, la CRP est produite dans la lésion athérosclérotique et par diverses cellules vasculaires, dont les cellules endothéliales. Afin d’élucider le rôle de la CRP vasculaire dans l’altération de la fonction endothéliale associée au syndrome métabolique, nous avons étudié la régulation de l’expression endothéliale de la CRP par les acides gras libres (AGL) et le rôle de la CRP endothéliale dans l’inhibition de la synthèse d’oxyde nitrique (NO) par les AGL. Nos résultats démontrent que :1) l’acide palmitique (PA) induit l’expression génique de CRP au niveau de cellules endothéliales aortiques humaines (HAECs) en culture et, augmente, de manière dose-dépendante, l’expression protéique de la CRP; 2) La pré-incubation des HAECs avec des antioxydants et des inhibiteurs de la i) protéine kinase C (PKC), ii) du facteur nucléaire-kappa B, iii) des Janus kinases et des protéines de transduction et de régulation de la transcription et iv) des protéines kinases activées par les mitogènes prévient l’effet stimulant du PA sur l’expression protéique et génique de la CRP; 3) Le traitement des HAECs par le PA induit une augmentation de la production des espèces réactives oxygénées, un effet prévenu par les inhibiteurs de la PKC et par l’AICAR(5-amino-4-imidazole carboxamide 1-β-D-ribofuranoside), un activateur de la protéine kinase activée par l’AMP; 4) L’incubation des HAECs en présence de PA résulte enfin en une diminution de la production basale endothéliale de NO, un effet abrogé par la préincubation de ces cellules avec un anticorps anti-CRP. Dans l’ensemble, ces données démontrent un effet stimulant du PA sur l’expression de la CRP endothéliale via l’activation de kinases et de facteurs de transcription sensibles au stress oxydatif. Ils suggèrent en outre un rôle de la CRP dans la dysfonction endothéliale induite par les AGL. / Atherosclerotic cardiovascular disease is the leading cause of death in western countries and the major complication of metabolic syndrome. It is now widely accepted that atherosclerosis is a chronic inflammatory disease and that inflammation plays a major pathogenic role in the initiation and progression of atherosclerotic disease. It has been demonstrated that increased serum levels of C-reactive protein (CRP), a protein of the acute phase and a major constituent of the innate immune response, is associated with increased cardiovascular risk and that, in both healthy subjects and diabetic patients, high CRP enhances the risk of cardiovascular morbidity and mortality. Several evidences suggest that CRP may not only be a cardiovascular risk marker but may also represent a direct pro-atherogenic factor. Endothelial dysfunction is a characteristic feature of early-state atherosclerosis and a role of CRP in the pathogenesis of endothelial dysfunction has been proposed. In addition to its systemic origin, CRP is produced in atherosclerotic lesions and by various vascular cells, including endothelial cells. To elucidate the role of CRP in endothelial dysfunction associated with the metabolic syndrome, we studied the regulation of endothelial CRP expression by free fatty acids (FFA) and the role of endothelial CRP as mediator of the inhibitory effect of FFA on nitric oxide (NO) production. Our results demonstrated that: 1) Palmitic acid (PA) induced CRP gene expression in cultured human arterial endothelial cells (HAECs) and increased CRP protein expression in a dose-dependent manner; 2) Pretreatment of HAECs with antioxidants and inhibitors of i) protein kinase C (PKC), ii) nuclear factor-kappa B, iii) Janus kinase and signal transducer and activator of transcription and iv) mitogen-activated protein kinases prevented the stimulatory effect of PA on CRP protein and gene expression; 3) Treatment of HAECs by PA led to an increased production of reactive oxygen species, an effect prevented by PKC inhibitors and by AICAR (5-amino-4-imidazole carboxamide 1-β-D-ribofuranoside), an AMP- activated protein kinase activator; 4) Decreased production of NO was finally observed in PA-treated HAECs, an effect prevented by preincubating endothelial cells with an anti-CRP. Overall, these data indicate a stimulatory effect of PA on endothelial CRP expression through the activation of oxidative stress-sensitive kinases and transcription factors. They further suggest a role of CRP in FFA-induced endothelial dysfunction.

Thrombin is the key protease that regulates hemostasis; the delicate balance between procoagulation and anticoagulation of blood. In clotting disorders, like deep vein thrombosis or pulmonary embolism, procoagulation is up-regulated, but propagation of clotting can be inhibited with drugs targeting the proteases involved, like thrombin. Such drugs however, have serious side effects (e.g., excessive bleeding) and some require monitoring during the course of treatment. The reason for these side effects is the mechanism by which the drugs’ act. The two major mechanisms are direct orthosteric and indirect allosteric inhibition, which will completely abolish the protease’s activity. Herein we sought an alternative mechanism called allosteric, partial inhibition, that has shown promise to truly regulate coagulation. Partial inhibition through allosteric mechanisms are well described for membrane-bound and oligomeric proteins. However proteases, specifically monomeric proteases (i.e., thrombin), have not shown this phenomenon until now. A small library of coumarin-based sulfated allosteric modulators (CSAMs) was synthesized to target a surface region called exosite 2; mainly composed of highly positively charged residues surrounded by hydrophobic patches. Studies revealed a non-competitive mechanism of binding with a range of IC50s between 0.2-58 µM combined with inhibitory efficacies (ΔY) between 22-73%; indicative of allosteric, partial inhibition. The KD was determined for the most potent compound (3g; IC50 = 0.2 µM, ΔY = 47%) at 0.15 µM. 3g was observed to bind at exosite 2 through unfractionated heparin competition and thrombin mutant studies. Additional computational studies were in agreement with the mutant and competition studies, showing the sulfate of 3g binding within a pocket containing R126 and R233. Fluorescence quenching and antithrombin inactivation rate studies described a conformational change to thrombin’s active site in the presence of 3g, supporting reduction of thrombin’s catalytic efficiency, without complete inhibition of thrombin’s proteolytic activities. Coupled enzyme assays and gel electrophoresis showed that in the presence of 3g, hydrolysis of fibrinogen (IC50 = 0.51 µM, ΔY = 94%) and protein C activation (IC50 = 1.7 µM, ΔY = 91%) is fully inhibited. Alternatively, FXIII activation was shown to be only partially inhibited by the presence of 3g, and FXI activation did not show any significant activation or inhibition. 3g was also shown to be active in human plasma and whole blood, but requiring much higher concentrations to induce an anticoagulant effect. Mice studies looking at the effects of 3g in vivo showed that even at high concentrations, showed no abnormal bleeding or any other irregularities. This work highlights a novel occurrence regarding thrombin’s allosteric functionality against multiple endogenous substrates. This library of compounds may be useful in the future development of allosteric inhibitors and probes that pose little to no risk of bleeding events by inducing partial inhibition.

La phospholipase A2 liée aux lipoprotéines (Lp-PLA2) est une biomarqueur de plusieurs maladies inflammatoires et une niveau sérique élevé est associé à l’instabilité de la plaque artérioscléreuse. Comme son nom l’indique, la Lp-PLA2 est liée aux lipoprotéines plasmatiques (LDL et HDL) et son rôle est de prévenir l’accumulation de phospholipides oxidés a la surface des lipoprotéines. Toutefois, les produits de dégradation des phospholipides oxidés par la Lp-PLA2 - le lysophosphatidyl choline par les acides gras oxidés peuvent aussi promouvoir l’inflammation. Mieux comprendre le métabolisme de la Lp-PLA2 pourrait nous permettre de mieux apprécier son rôle dans la formation d’une plaque artérioscléreuse instable, car des études antérieures ont démontré une forte expression de la Lp-PLA2 dans la plaque. De plus, il existe une forte corrélation entre les niveaux et l’activité plasmatiques de la Lp-PLA2 et la maladie coronarienne, les accidents cérébraux-vasculaires et la mortalité cardiaque. L’inhibition de la Lp-PLA2 avec une petite molécule, le darapladib, n’a pas démontré de bénéfice sur les évènements cardiovasculaires dans deux études cliniques. Cette thèse présentera d’abord une revue de la littérature sur la Lp-PLA2 et les maladies cardiovasculaires et les deuxième et troisième chapitres, une étude clinique réalisée sur des patients avec un syndrome coronarien aigu. / Lipoprotein associated phospholipase A2 (Lp-PLA2) is a biomarker of several inflammatory diseases and syndromes. An elevated Lp-PLA2 level is associated with unstable atherosclerotic plaques. Bound to plasma lipoproteins (LDL and HDL), Lp-PLA2 prevents the formation of biologically active oxidized phospholipids on their surface such as oxidized phosphatidylcholine (oxPC). Nevertheless, the products of Lp-PLA2 action, lysophosphatidylcholine (LPC) and non-esterified fatty acids (NEFA) are both known to aggravate inflammation. Thus, understanding the metabolism of Lp-PLA2 could help us better understand its role in plaque formation, as studies have shown high expression of Lp-PLA2 and LPCs in unstable plaques. Moreover, studies showed correlation between increased Lp-PLA2 mass and activity and increased risk of coronary artery disease, stroke, and death. The inhibition of Lp-PLA2 with a small molecule, Darapladib, has not demonstrated benefit in reduction of cardiovascular events in two clinical studies. Here, the first chapter will focus on Lp-PLA2 and cardiovascular disease in man, highlighting the latest updates in the literature. The second and third chapters will introduce experimental work on Lp-PLA2 in the setting of acute coronary syndrome.