Protective effect of sildenafil on the genotoxicity and cytotoxicity in apolipoprotein E-deficient mice bone marrow cells.

BACKGROUND: The pharmacological inhibitor of phosphodiesterase 5 (PDE5), sildenafil, is a promising candidate for antioxidant therapy that can result in cardiovascular protection. In addition to its known effects on the cardiovascular system, hypercholesterolemia leads to increased oxidative stress and DNA damage in the bone marrow, which is a non-classical target organ of atherosclerosis. In the present study, we evaluate oxidative stress and assess the effect of genomic instability on cell cycle kinetics in atherosclerotic animals and determine if sildenafil reverses these detrimental effects in bone marrow cells. METHODS: Experiments were performed in male wild-type (WT) and apolipoprotein E knockout mice (apoE(-/-)) (9 weeks of age). apoE(-/-) mice were randomly distributed into the following 2 groups: sildenafil-treated (40 mg/kg/day for 3 weeks, n = 8) and vehicle-treated (n = 8), by oral gavage. After treatment, bone marrow cells were isolated to assess the production of superoxide anions and hydrogen peroxide, determine cell cycle kinetics and evaluate the presence of micronucleated cells. RESULTS: Sildenafil treatment reduced the cytoplasmic levels of superoxide anion (~95% decrease, p < 0.05) and decreased hydrogen peroxide (~30% decrease, p < 0.05). Moreover, we observed protective effects on the DNA of bone marrow cells, including normal cell cycling, decreased DNA fragmentation and a diminished frequency of micronucleated cells. CONCLUSION: Our data reveal that the excessive production of ROS in atherosclerotic mice overcome the DNA repair pathways in bone marrow cells. The novelty of the present study is that the administration of sildenafil reduced ROS to baseline levels and, consequently, reverted the DNA damage and its outcomes in bone marrow cells.

Increased oxidative stress and apoptosis in peripheral blood mononuclear cells of fructose-fed rats.

BACKGROUND: Measuring of oxidative stress in peripheral blood mononuclear cells is a suitable model of dietary induced systemic oxidative stress. Thus, we aimed to evaluate whether a chronic high fructose intake could induce oxidative damage in peripheral blood and bone marrow mononuclear cells of rats. METHODS: Animals were randomly assigned to the following groups: Control group (standard rat chow and tap water n=8), and Fructose group (standard rat chow and a 10% fructose solution in the drinking water n=8). Reactive oxygen species and cytokines were measure using flow cytometry in peripheral blood and bone-marrow mononuclear cells. Apoptotic cell death and the advanced oxidation protein products (AOPP) were also determined. RESULTS: We observed a significant increase in ROS production in peripheral blood mononuclear cells of fructose group as compared to control rats. Apoptosis and the AOPP were higher in those animals underwent high fructose intake. Serum levels of IL-6 and IL-12 were also increased after 12 weeks of high fructose intake. CONCLUSION: We concluded that fructose intake leads to systemic oxidative stress and pro-inflammatory condition which affect peripheral blood mononuclear cells and bone-marrow mononuclear cells viability.