Atherosclerosis is one of the most common diseases and the main cause of death in developed Western societies. The pathogenesis of this disease can be explained based on the "oxidative modification hypothesis" which proposes that oxidation of LDL represents a initial key event. However, we do not know exactly how and where LDL oxidation occurs. Recently we have shown in an experimental model with high susceptibility to atherosclerosis (LDL receptor knockout mice, LDLR-/-) that mitochondria are relevant sites of generation of cellular oxidative stress. This occurs as a result of a low antioxidant capacity of NADPH-dependent enzyme systems in LDLR-/- mitochondria compared to control mice (C57BL6/Unicamp). We proposed that the decrease in content of reduced nucleotides (NADPH) in the mitochondria of LDLR-/- mice was due to their increased consumption by of the high rate of lipogenesis in hepatocytes of these animals. Considering that the LDLR-/- mice have a C57BL6/J background (Jackson Laboratory), they also present another genetic deficiency in the gene that codes for the mitochondrial NADP-transidrogenase (NNT). Therefore, there is a possibility that the decrease in NADPH content might be the consequence of the NNT deficiency instead of the increased cholesterol synthesis. In this project we will investigate the mechanisms involved in mitochondrial redox changes of the three mice lines: C57BL6/Unicamp (intact NNT and LDLR), C57BL6/J (NNT mutation) and LDLR-/- (LDLR and NNT mutations). The results may explain the actual mechanisms involved in the oxidative stress of LDLR-/- hypercholesterolemic mice.
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