Nitric oxide (NO) is considered an anti-atherogenic molecule by its multiple actions in maintaining vascular integrity. However, when it reacts with superoxide radicals produced under oxidative stress conditions, it generates peroxynitrite, a potent pro-oxidant and cytotoxic molecule. On the other hand, NO* may have antioxidant properties through terminal reactions with lipids generating less reactive nitrated products. Recently, we showed in an atherosclerosis prone experimental model (hypercholesterolemic LDL receptor knockout mice) that the mitochondria are relevant sources of cellular oxidative stress due to a low antioxidant capacity of NADPH-dependent enzymes when compared to control mice. In these animals, inhibitors of NO synthase decreased susceptibility to mitochondrial permeability transition, while in the control mice, these inhibitors stimulated the opening of the permeability transition pore, a condition that may lead to cell death. In addition to the LDL receptor deficiency, the hypercholesterolemic mice have also mitochondrial NADP-transidrogenase deficiency, and therefore, may have low generation of NADPH from NADH. Thus, in this project we propose to clarify whether the effect of the inhibitor of NO synthase is related to the redox state of NADP(H), which can be modified by the increased endogenous cholesterol synthesis or by the deficiency of mitochondrial transidrogenase. These results may provide a better understanding of the molecular mechanisms involved in the mitochondrial nitroxidative stress in familiar hypercholesterolemia that can be useful for therapeutic approaches.
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