Importancia de biomarcadores inflamatorios en la ateroesclerosis subclínica asociada a síndrome metabólico: modelo experimental y clínico

Tesis-Doctor en Medicina y Cirugía-Universidad Nacional de Córdoba. Facultad de Ciencias Médicas, 2014164 p.Existen evidencias que asocian biomarcadores inflamatorios con síndrome metabólico (SM), insulinoresistencia y enfermedad aterogénica subclínica (ATS), pero no está clara su interrelación y como contribuirían al desarrollo de estas patologías multisindrómicas. El componente inflamatorio sería la vía final común reflejada por la disfunción endotelial y la inducción de estrés oxidativo. Se diseñó un modelo experimental de SM mediante la administración de fructuosa al 10% diluída en agua de bebida por 6 semanas y de ATS inducida por hiperfibrinogenemia (HF) en diferentes períodos experimentales. Se determinó en todos los grupos estudiados: glucemia, insulinemia, perfil lipídico, cálculo de HOMA (homeostasis model assessment) y se cuantificaron por espectrofotometría biomarcadores inflamatorios y de estrés oxidativo: fibrinógeno, oxido nítrico (NO), L-citrulina, adiponectina y superóxido dismutasa (SOD). Se analizó por microscopia óptica la anatomía patológica de aorta torácica e hígado. Se determinaron las probables alteraciones morfológicas mitocondriales en células musculares lisas aórticas por microscopia electrónica y para valorar funcionalidad se determinó la actividad enzimática de Citrato Sintasa y los complejos I, II, III y IV de la cadena respiratoria mitocondrial.There is evidence to associate inflammatory biomarkers with metabolic syndrome (MS), insulin resistance and atherogenic subclinical disease (ASD), but it is unclear their interrelationship and how would it contribute to the development and progression of these multisindromical pathologies. The inflammatory component would be the final common pathway reflected by endothelial dysfunction and induction of oxidative stress. An experimental model of MS was designed by administering diluted fructose to 10% in drinking water for 6 weeks and ASD induced by hyperfibrinogenemia (HF) in different experimental periods. Glucose, insulin, lipid profile and HOMA calculation (homeostasis model assessment) was determined in all groups studied. Inflammatory and oxidative stress biomarkers: fibrinogen, nitric oxide (NO), L-citrulline, adiponectin and superoxide dismutase (SOD) were quantified by spectrophotometry. Thoracic aorta and liver histopathology were analyzed by optical microscopy. Probable mitochondrial morphological changes in aortic smooth muscle cells were determined by electron microscopy and functional alterations were measured by the enzymatic activity of citrate synthase and complex I, II, III and IV of the mitochondrial respiratory chain. 72 male rats, Wistar strain, distributed in 6 groups (n12): control, HF for 30 and 60 days, MS, MS + HF 30-day and 30-day HF + MS. In addition, to assess the behavior of proinflammatory, prooxidatives and antioxidants biomarkers in patients with MS, a clinical model was designed. For statistical analysis, quantitative variables were tested with MANOVA. Post hoc test used was Hotelling. The correlation degree between the biomarkers was established with the Pearson correlation coefficient. Axiovision 4.8 program was used to analyze mitochondrial morphology. A p<0.05 was considered in all cases. Groups with MS experimentally induced showed hyperglycemia, hyperinsulinemia, increased HOMA and hypertriglyceridemia typical of this syndrome. All groups with MS and HF in the differents experimental periods showed significant difference of the biomarkers associated with ASD pathognomonic changes. The liver sections of the groups with MS compatible changes with nonalcoholic liver disease were observed. In all groups were observed mitochondrial morphological changes associated with an enzymatic activity progressive decrease of citrate synthase and respiratory chain reflecting mitochondrial dysfunction. Patients with MS showed biomarkers levels significantly altered with HF, SOD increase and NO decrease. The increased cardiovascular risk MS patients have might be explained by the atherogenic changes. The impairment of mitochondrial function would be the main unifying mechanism of various risk factors such as metabolic syndrome and atherogenesis. The implementation of early biomarkers in ischemic vascular disease and MS would be a valid strategy in early diagnosis in patients and to overcome barriers in the management of these diseases with high epidemiological impact in countries with low budget in health.Fil: Tarán, Mariana Denise. Universidad Nacional de Córdoba. Facultad de Ciencias Médicas; Argentina.Otras Ciencias Médica