Identificador: TDX:608
Autores: Cabré Llobet, Anna
Resumen:
Atherosclerosis is a progressive disease characterized by an accumulation of lipids in the subendothelial wall. Experimental evidence suggest that lipid peroxidation, inflammatory response and thrombogenic processes play an important role in the pathogenesis of atherosclerosis and its clinical complications. Oxidized LDL particles, some of their oxidative compounds, elevated levels of proinflammatory cytokines and tissue factor (the main inducer of thrombosis) have been detected in plasma of patients with high cardiovascular risk. It has also been reported the presence of all these components in human atherosclerotic plaques where also has been observed an accumulation of inflammatory cells. However, no direct evidence exist about a direct relation between lipid peroxidation and inflammation. A recent interesting finding is the possible role of PPAR in atherosclerosis. PPAR is the nuclear receptor target of thiazolidinediones, drugs used in the treatment of non insulin dependent diabetes mellitus. These drugs have shown a net antiatherosclerotic effect in animal models and in clinical studies in humans. In vitro experiments have shown that thiazolidinediones may have an important antiinflammatory action. PPAR is overexpressed in atherosclerotic plaques where colocalizes with oxidized lipids. Recently, oxidized LDL has been pointed as an important source of PPAR ligands.The work presented in this thesis shows new knowledge of the lipid peroxidation role in the pathogenesis of atherosclerosis emphasized in the action on inflammation and thrombosis. In summary, the obtained results support the theory that lipid oxidative modification plays an important role in the progression of atherothrombotic disease.Results show that the apolar aldehyde 2,4-decadienal, an end product of the oxidation of the main polyunsaturated fatty acids present in LDL, contributes to the well-known toxicity of oxidized LDL in human smooth muscle cells. The cytotoxic effect observed may not be promoted by an apoptotic state because the characteristic DNA ladder is not induced. 2,4-decadienal and hexanal, another apolar aldehyde, at non cytotoxic concentrations produce cell growth arrest and decrease p53 and c-myc mRNA levels, genes involved in the regulation of apoptosis. These results suggest that the cytotoxicity of aldehydes may be explained by cell necrosis.On the other hand, both aldehydes increase tissue factor mRNA and protein levels. We suggest that this effect may be produced through the activation of the transcription factor AP-1 formed by the complex cFos-cJun and by previous synthesis of c-Fos. This effect is prevented by a pretreatment with simvastatin, a hypolipidemic drug with antioxidant and antithrombotic properties.Concerning PPAR implication in atherosclerosis, 1) we have identified two PPAR response like elements in the human TNF promoter which suggest a direct link between PPAR and inflammation. This study adds more data in the knowledge of the mechanism of action of thiazolidinediones and describes a new pathway to modulate TNFexpression; 2) we propose that 2,4-decadienal may be a PPAR mediator in the atheromatous plaque based on our results that show PPAR activation by 2,4-decadienal. 2,4-decadienal increases PPAR translocation from the citosol to the nucleus and increases the transcription regulated by PPAR; 3) we also show evidence that the non desirable proatherosclerotic effect (CD36 induction) of thiazolidinediones would not be produced in type 2 diabetic patients. These patients have high levels of circulating fatty acids and our results show that darglitazone, a thiazolidinedione, in the presence of fatty acids neither alters CD36 expression in human monocytes and macrophages nor modifies macrophage lipid content.
Repositori URV