ARTERIOSCLEROSIS AND ATHEROSCLEROSIS

Author: RIBAS SERRA VICENT.
Year: 2004.
University: AUTÓNOMA DE BARCELONA.
Place of defense: DEPARTAMENTO DE BIOQUÍMICA Y BIOLOGÍA MOLECULAR.
Place of preparation: ESCUELA DE POSTGRADO UAB.

Summary: The apolipoproteins most abundant of HDL are apoA-Iy the apoA-II. The plasma concentration of apoA-I are inversely related to the risk of coronary heart disease and its role in HDL is well known. The apoA-I has a very important structural role in HDL, interacts with receptors causing the flow of HDL cholesterol in cell membranes and is cofactor of the LCAT. Instead, the role of apoA-II in lipoprotein metabolism and the development of atherosclerosis is less well known. The line of transgenic mice with more expression of apoA-II human (line 11.1) fed atherogenic diet develops combined hyperlipidemia, and low HDL significant increase susceptibility to atherosclerosis. The transgenic mice of apoA-II human line 11.1 showed a large increase in the area of staining for epítopos derived from oxidation in these injuries over the controls. In the study of the antioxidant properties of HDL mice 11.1, they had a lower capacity for protection against lipoprotein oxidation with apoB, which controls the HDL mice and transgenic 25.3 (low expression of apoA-II) . The HDL of transgenic mice 11.1 submitted an altered composition with a lot of apoA-Ii human, and decreased apoA-I, PON1 and PAF-AH, which probably explains the slightest protection against oxidation that provide these HDL. These replace the HDL particles are not due to changes in the transcription of genes apoA-I, PON1, PAF-AH, LCAT. However, in vitro tests showed that the apoA-II human is capable of moving the PON1 of HDL particle. The change in the antioxidant capacity of HDL of transgenic 11.1 explain, at least in part, the increased susceptibility to atherosclerosis in these animals in atherogenic diet. The study of the capacity of these transport back to make HDL cholesterol, the results showed that despite the partial deficiency of presenting HDL, the transgenic mice 11.1 did not show a significant change in the rhythm of reverse cholesterol transport specific macrophages, for the mice controls. Thus, the susceptibility to atherosclerosis in mice transgenic 11.1 fed atherogenic diet, does not appear to be attributable to a decrease in the reverse cholesterol transport specific macrophages.

Author: PERÉZ DE PRADA M. TERESA.
Year: 2004.
University: COMPLUTENSE DE MADRID.
Place of defense: FACULTAD DE MEDICINA.
Place of preparation: FACULTAD DE MEDICINA. UNIVERSIDAD COMPLUTENSE.

Summary: Atherosclerosis is a complex multifactorial disease in which the accumulation of lipid material on the wall of glass, its oxidation, and the disruption of the metabolism of lipoproteins are factors that lead to the genesis of atherosclerotic lesions. It is a chronic inflammatory process that causes heart disease, stroke and peripheral vascular, and that is the leading cause of death in Spain and in many other Western countries. Many work in the literature deemed atherosclerosis as a local process, and some suggest a link between the overproduction of cortisol or exogenous administration of this molecule, and the process aterosclerótico. The cortisol, the major glucocorticoid (GC) produced by the human adrenal cortex, is the final product of the axis hipotálamo-hipófisis-glándula adrenal (HPA), the main system endogenous anti-inflammatory. In addition, there is evidence linking a poor response of HPA axis with the development of disease. However, the study of the response of the HPA axis damage to vascular endothelium, and the response of the same genesis and progression of the disease, has not been addressed previously. To address this issue will be resorted to using an experimental model in rabbits to which were induced the appearance of atherosclerotic lesions by feeding diets high in cholesterol. This model allowed to study the behavior of the HPA axis during the initiation and progression of atherosclerotic lesions. Due to the nature of record inflamatoria-fibroproliferativa chronic process aterosclerótico, monocytes have a key role both in its genesis as in the progression of atherosclerotic lesions. The recruitment of monocytes into the area of injury seems to be one of the key elements in the formation of the lesions. However, this is essential in the repair of damage caused in the vascular endothelium. The monocytes are attracted by a gradient quimiotácticas substances that are secreted in the area of the injury. The oxidized low-density lipoprotein (LDLox) are one of the key players quimioatrayentes involved in the recruitment of monocytes peripherals. Glucocorticoids inhibit the migration of monocytes into LDLox, which valued the ability to migrate peripheral monocytes from healthy subjects and patients with coronary atherosclerosis compared to LDLox quimiotácticas and other substances, as well as the effect that treatment with cortisol exercises on this capacity. The GCs carry out their duties through the intracellular binding to its receptor, hGR. Two isoforms have been identified, Hgr alpha and hGR beta, which shows a high homology between their sequences. The translocation of the isoform hGR alpha occurs after the union of the hormone. The isoform hGR Beta has no hormone binding domain and resides in the nucleus. In certain human diseases involving chronic inflammation, have come to make a connection between high levels of hGR and the inability of GCs to exert their effects on the target tissues. For that reason, we measured levels of expression of hGR alpha and hGR beta in peripheral monocytes from healthy subjects and in patients with coronary atherosclerosis. Taking into account the differences in levels of LDLox between healthy subjects and patients with atherosclerosis, it was felt important to assess the effect of this difference in the burden of intracellular lipid peripheral monocytes in both groups as well as 8 the capt 1f6 ation and subsequent translocation the complex hormona-receptor from the cytoplasm to the cell nucleus.

Author: HINCHADO CABALLERO GLORIA.
Year: 2004.
University: EXTREMADURA.
Place of defense: FACULTAD DE MEDICINA.
Place of preparation: FACULTAD DE MEDICINA.

Summary: There are numerous data in the literature that relate oxidative stress with the pathophysiology of many diseases and aging. The increase in life expectancy of women means that at least one third of his life happen in the climacteric. Because of the endocrine changes that it entails, and they produce long-term increased osteoporosois and atherosclerosis have been postulated different drug therapies that improve these complications and the symptoms that accompany menopause (hot flashes, etc.â |) Notwithstanding these treatments are not without side effects, mainly cancer types (ca.endometrial and breast). OBJECTIVE Therefore, the objective of this study was to explore the role that exercise this kind of treatment (estrogen, SERM (raloxifene) and tibolona) on the systems oxidation antioxidación both overall (plasma) as a body of specific performance ( uterus). MATERIALS AND METHODS The study was conducted on 75 female rats wistar adult separated into five groups of fifteen rats. One group was left to evolve without any intervention, while the rest were surgically castrated. Castradas The rats were divided in turn into four groups. While one was left without any treatment, the others were treated respectively with: 6ug/dia of 17 beta-estradiol, 2mg/dia raloxifene and 0.5 mg / day tibolona for thirty days. Completed treatment proceeded to the extraction of blood and uterus. We measured plasma levels of estradiol, hemoglobin concentration in blood and total protein in the uterus. We measured the levels of malondialdehyde as an expression of lipoperoxidación and catalase and superoxide dismutase as a sign of the activity of antioxidant systems. Results were analyzed with the statistical package Statistica version 6, realizándose a study estadistíco descriptive, non - parametric test application (Kruskal-Wallis) and a discriminant analysis of all variables. RESULTS plasma level, the highest standards of malondialehido was found in the group of rats castradas, although there were no significant differences in any of the groups studied. The catalase activity was significantly lower in the groups treated with castration and estrogen ad suprafisiológicas sis. With regard to the uterus, increased levels of malondialdehyde were found in the group treated with raloxifene and minors in the group treated with tibolona (p less 0007). The activity of catalase is highest in the group treated with raloxifene and the lowest in the group treated with estreogenos, there are significant differences between the group treated with estrogen and the rest of the groups. With regard to the activity of superoxide dismutase is precisely the group treated with raloxifene, which presents the reduced activity of this enzyme. CONCLUSIONS level plasma estradiol treatment at doses suprafisiológicas castration and generate an increase of oxidative stress. At the uterine Raloxifene and tibolona behave in a different way: that while raloxifene has an impact prooxidativo, tibolona of dosage and time administered not. Concentrations uprafisiológicas estradiol induces in the uterus an important oxidative stress.

Author: BUSTAMANTE RODRÍGUEZ EDUARDO.
Year: 2004.
University: ZARAGOZA.
Place of defense: HOSPITAL UNIVERSITARIO MIGUEL SERVET DE ZARAZOGA.
Place of preparation: FACULTAD DE MEDICINA.

Summary: INTRODUCTION The relationship between alterations in lipid metabolism and cardiovascular disease has been established with absolute clarity in recent years. It is known, the relationship between the decrease in the concentration of high-density lipoprotein associated with cholesterol (HDL-C) and increased risk of coronary heart disease. However, by their biochemical and functional heterogeneity, is not fully clarified the biological and clinical significance of abnormal these lipopartículas. ASSUMPTIONS Patients healthy, which detected low levels of HDL-C have an increased propensity to suffer from cardiovascular events in the long run. The biochemical and functional heterogeneity of the HDL particle comprises a distinct evolution in the development of the disease caridovascular and more specifically coronary disease. OBJECTIVES To identify the cardiovascular risks of different forms of hipoalfalipoproteinemia. Knowing whether the isolated predisposes or low HDL-C are associated with cardiovascular disease, non-cardiovascular, neoplastic not. Knowing whether the subjects with low HDL-cholesterol, triglycerides (TG) and high LDL-C system are increased cardiovascular risk. MATERIALS AND METHODS Prospective, observational case-control. Coming from a number of companies has been selected a sample of workforce with low HDL-C (less 40 mg / dl) and other controls. All of them men aged over 20 years and free of cardiovascular disease at the time of recruitment. It was followed up from 1990 to 2003 and assessed the development of cardiovascular disease making assumptions contrast, mean, survival analysis and multivariate analysis. RESULTS After graduation the bulk sample comprised 777 subjects. Cases = 395. Controls = 382. Average age: 44.23 years (95% CI; 43.63-44.8 (. Events: 42 subjects suffered from ischemic heart disease (ICC), 4 lctus and 9 peripheral vascular disease (PAD). Mean systolic blood pressure (TAS), diastolic (TAD ) and body mass index (BMI) was higher in the case group compared to controls (respectively p = 0,003, p less 0,001, p = 0.018). was found also were higher average values of TAS (p less 0,001 ), CAS (p less 0,001) and BMI (p = 0.02) in the group of subjects who subsequently suffered ICC. Samples were homogeneous in that respect to total cholesterol (GCC), and LDL-C significant differences for TF , it being clearly higher among group of cases (p = 0.022). subjects who subsequently developed ICC average HDL-C was significantly lower (p less 0,001) and triglyceride higher (p = 0.024). those who developed PAD average HDL-C was significantly lower (p = 0.003). was a clear predominance of type ICC events between cases (n = 32) compared with controls (n = 9) (p less 0,001) with a relative risk 4.11, as well as events type PAD (cases: n = 9, controls: n = 0) (p = 0.002). was no difference in the type of ICC. Nor in connection with the non-cardiovascular mortality or the development of malignancies. There was a predominance of smokers with low HDL-C (p less 0,001). There was a highly significant relationship between the group of cases and hypertriglyceridemia (p less 0,001) but not demonstrated difference between being with low HDL-C and without hypertriglyceridemia companion even with normal LDL-C. HDL-C was significantly correlated with TG (index =- 0.47, p less 0,001). Kaplan Meier The study showed a poorer survival in the group of cases concerning the controls regarding CPI (p = 0.0001) and PAD (p = 0.0079), and was shown to further divided into 6 strata according to perecentiles of HDL-cholesterol, the lower the HDL-C was worse survival (p = 0.0102) . There was no difference in stroke. Nor was no difference in the survival of subjects with low HDL-C with and without hypertriglyceridemia. dyslipidaemia isolated with worse survival in terms of the ICC was H 8 DL-C ai 689 slado followed of the LCL-C high isolation. There were no events in subjects with high TG isolated. Cox regression models revealed that the most significant variables were the HDL-C, snuff and Tas. OR be low HDL-C is 3.9 (p less 0,001) and smoking 1.9 / p = 0.032). HDL-C as a continuous variable won an OR in the model 0,941 (p less 0,001). CONCLUSIONS cardiovascular risk is increased in the hipoalfalipoproteinemia patients healthy. subjects with low HDL-C increased by 4 registration ICC to 10 years. low HDL-cholesterol associated with hiperTG showed no increased cardiovascular risk. associated with low HDL-C The other dislipemias showed no pose an increased risk cardiovascular the low HDL-C isolated. The lower the HDL-cholesterol, lower risk. not demonstrated relationship between subjects with HDL- low mortality and coronary or non - malignancies. There is a marked tendency to TG high among low HDL-C . Increasing 1mg/dl the HDL-C reduced the risk of a 5.9% CPI to 10 years.

Author: BERTRAN FERRÚS NURIA.
Year: 2005.
University: ROVIRA I VIRGILI.
Place of defense: FACULTAT DE MEDICINA I CIÈNCIES DE LA SALUT.
Place of preparation: FACULTAT DE MEDICINA I CIÈNCIES DE LA SALUT REUS.

Author: CASANÍ ARAZO LAURA.
Year: 2005.
University: AUTÓNOMA DE BARCELONA.
Place of defense: INSTITUT CATALÁ DE CIÉNCIES CARDIOVASCULARES.
Place of preparation: CENTRE RECERCA CARDIOVASCULAR-ICCC-CSIC. HOSPITAL STA CREU I ST PAU-UAB. BARCELONA.

Summary: Cardiovascular diseases are the leading cause of morbi / mortality in the industrialized countries and in developing countries. The substrate pathological most important in the etiology of these diseases is the formation d le aplaca ateromatosa and subsequent thrombosis, boosted both by the presence of risk factors such as dyslipidemia, smoking and hypertension. One of the main objectives in the prevention of cardiovascular disease is the treatment of hyperlipidemia. This thesis examines the two main strategies for the prevention of cardiovascular disease in the reduction in serum cholesterol: changing diet, focusing on a single component of the Mediterranean diet (red wine), and treatment with lipid-lowering drugs (pravastatin). The objective of this thesis is to investigate the molecular mechanisms of action of both preventive strategies inhibition of thrombotic risk in the experimental model of hypercholesterolemia-induced pig diet. To evaluate the effect of antithrombotic red wine and the paravastatina been studied platelet deposition, unleashed after infused substrates vascular counterparts in a perfusion chamber or cylindrical reactor flow (Badimon L. 1987). The animals were fed for 100 days with feed hipercolesterolémico that simulates the diet of industrialized countries (2% cholesterol and 20% saturated fat). We studied three doses of red wine (20.30 and 40g alcohol / day), administered along with the daily ration of feed, between different groups of animals and compared with the control group (only think hipercolesterolémico without intake of wine). At the end of the experimental period and after analysis biochemical and hematological animals were subjected to the study of vascular thrombosis triggered substrates for moderate and severely injured. We used two types of cameras infusion to obtain the desired flow speeds, 212 s-1 (slow speed, typical of stenosed coronary arteries) 7y 1690 s-1 (high speed, model stenosed coronary arteries). We also analyzed changes in the translocation of RhoA in platelets and the expression of tissue factor (FT) in monócitos. The deposition paquetaría on the wall was significantly decreased in animals that had ingested came along with the feed, compared with the control animals. The expression of RhoA in the cytoplasm platelet (inactive form) increased in the groups with intake of wine, while the expression on the platelet membrane (active) fell. The expression of FT in monócitos stimulated with LPS (lipopolysaccharide) decreased in the animals that had ingested wine. The cholesterol levels were not significantly different among the study groups. In the next study animals were fed for 100 days with feed hipercolesterolémico, but during the past 50 days a group was treated with a dose of 5 mg / kg of pravastatin and the other with a placebo. Both groups were compared with the control group (animals for 100 days were fed with feed normocolesterólemico). At the end of the experimental period was evaluated using a thrombotic risk guiding flow (camera) Second Generation, a profusion of camera that allows a speed shearing 212s-1 with stenosis of 70% in the central zone (L Badimon, 1991 ). We also evaluated the expression of RhoA in the platelet membrane and the FT in the vascular wall. Treatment with pravastatin significantly inhibits platelet deposition on injured vascular wall (light and severely) and is not a significant difference in levels lasmáticos cholesterol between the two groups hipercolesterolémicos. Besides the pravastatin reduced the expression of 8 RhoA in 4cf the platelet membrane and the expression of FT in the vascular wall of treated animals. We conclude that moderate consumption of wine and treatment with pravastatin are able to decrease the risk of thrombotic conditions sustained hypercholesterolemia, ie without reducing the external input of cholesterol and saturated fats. This means that both also act independent mechanisms for the decrease in plasma lipids, suggesting a direct effect on the activity of the platelet and interacciónplaqueta-pared vascular.

Author: ULIAQUE CUGAT KATIA.
Year: 2006.
University: ROVIRA I VIRGILI.
Place of defense: FACULTAT DE MEDICINA.
Place of preparation: FACULTAT DE MEDICINA.

Summary: The cardiovascular protective effects attributed to a Mediterranean-type diet rich in monounsaturated fatty acids, produced by virgin olive oil, are due, in part, to an increase or maintenance of the plasma concentrations of cholesterol are high-density lipoprotein (HDL ). However, it was not known if the mechanisms behind these concentrations are induced by an increase in production of apolipoprotein (apo) AI (apo majority in the HDL), a decrease of degradation or catabolism of this apoA-Ioa both parameters simultaneously. The most physiologically evaluate the production and degradation of a man in apo is through kinetic studies using stable isotopes, a technique that is not implemented in our country. Objective: To implement the kinetic studies of the apoA-I, apoA-II of HDL and the apo B-100 of VLDL1, VLDL2, IDL and LDL. Applying this methodology to compare the effects of a Mediterranean diet rich in virgin olive oil with a diet low in fat (STEP II) on the metabolism of HDL and low-density lipoprotein (LDL). Design: randomized crossover study of 4 weeks of dietary intervention, with washout period. 10 volunteers, men healthy, moderately hipercolesterolémicos have followed two diets. This study was approved by the Committee on Ethics and Clinical Research at the University Hospital Sant Joan de Reus. Instrumentalización: kinetic study by injection and infusion stable 2H3-L-leucina in isotope form of an initial bolus and infusion for 16 h, at the end of each diet. Separation by ultracentrifugation of the different fractions lipoproteicas. Detection of isotope incorporation by GC-MS. The data obtained were analyzed by the program SAAM II. The kinetic studies of apoA-Iy apoA-II have been refined and made our Research Unit in Reus. Studies of apo B-100 and kinetic modeling of the data has been made in collaboration with the research group of Vascular Biochemistry Section, Division of Cardiovascular & Medical Sciences, Royal Infirmary, University of Glasgow, Glasgow). Results: The Mediterranean diet produces higher levels of apoA-I plasma. Se han realizado 17 kinetics, but due to the complexity of the methodology, in this thesis presents the results of a group of 7 kinetic that have already been analyzed by GC-MS. Despite the low number of kinetic, there are certain trends. The Mediterranean diet has a higher rate of production apoA-I of HDL compared with the diet STEP II. The Mediterranean diet has a higher rate of production and catabolism of apo B-100 of LDL compared with the diet STEPII. Conclusions: It has implemented the methodology of the studies of kinetic with stable isotopes of apoA-Iy apoA-II of HDL and apo B-100 of VLDL1, VLDL2, IDL and LDL. The determinant of the highest concentrations of apoA-I plasma is a higher rate of production of this Apo and not differences in their catabolism. Inputs from the kinetics of lipoproteins move forward in the mechanisms involved in lipid vascular disease and provide new aspects on the nutritional and pharmacological targets.