Likewise, the liver was fo cused due to its metabolic importance and to its high susceptibility our website to cumulative oxidized products of DNA. Furthermore, Folkmann et al. showed that dyslipidemic apoE mice suffer from hepatic oxidative stress genotoxicity and this could be due to dysfunction of the lipid metabolism. The novelty of the present study is that it was possible Inhibitors,Modulators,Libraries to reduce DNA damage in MNC and liver cells of apoE mice by chronic inhibition of PDE5 with sildenafil, Inhibitors,Modulators,Libraries even under conditions of hypercholesterol emia, possibly by the same antioxidative mechanisms above commented. This finding supports the idea that sil denafil is a promising novel pharmacologic strategy to avoid tissue damage induced by oxidative stress as previ ously reported by us and others, thus open ing the way for translational studies about the protection of DNA in different clinical conditions.

Study strength and limitations A major strength of our study is the evaluation of the beneficial effects of sildenafil on genotoxicity in the apoE mouse, which exhibited a protective action against DNA damage in MNC and liver cells. However, this study has some limitations. Although it has been demonstrated that sildenafil administered for 3 weeks Inhibitors,Modulators,Libraries reduces oxidative stress in smoke induced erectile dys function in C57BL6 mice and has been considered a novel therapeutic strategy to repair the endothelial dys function in apoE mice, we cannot predict whether such beneficial effects on genotoxicity and oxidative stress are long lasting in atherosclerosis.

Another limita Inhibitors,Modulators,Libraries tion of the present study is that we did not include in our protocol a group Inhibitors,Modulators,Libraries of apoE under a regular chow. Conclusions ApoE mice are characterized by a systemic oxidative stress, as demonstrated by MNC high levels of super oxide anion production that leads to DNA damage. In these animals, hepatic oxidative stress is also substantial, when compared to control normocholesterolemic animals. The treatment with sil denafil was efficient to decrease the levels of superoxide anion in MNC and the DNA fragmentation in both MNC and liver cells in apoE mice. Thus, we propose that sil denafil may offer a new perspective to the use of PDE5 in hibitors to protect against DNA damage observed in atherosclerosis, independent of hypercholesterolemia.

Methods Animals Experiments were performed in male WT and apoE mice obtained from the Laboratory of Trans genes in the Health Sciences Center at the Federal Uni versity selleck of Espirito Santo, Brazil. Animals were housed in individual plastic cages with a controlled temperature and humidity and were exposed to a 12 12 h light dark cycle. All experimental procedures were performed in accordance with the guidelines for the care and handling of laboratory animals as recom mended by the National Institutes of Health, and study protocols were previously approved by the Institu tional Animal Care and Use Committee.