title: Protective effect of sildenafil on the genotoxicity and cytotoxicity in apolipoprotein E-deficient mice bone marrow cells.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Laboratory of Translational Physiology, Health Sciences Center, Federal University of Espirito Santo, Vitoria, Brazil.
authors.forename: Franciane P
authors.initials: FP
authors.lastname: Bernardes
authors.affiliation: Laboratory of Translational Physiology, Health Sciences Center, Federal University of Espirito Santo, Vitoria, Brazil.
authors.forename: Alan T
authors.initials: AT
authors.lastname: Batista
authors.affiliation: Federal Institute of Education, Science and Technology (IFES), Vila Velha, ES, Brazil.
authors.forename: Marcella L
authors.initials: ML
authors.lastname: Porto
authors.affiliation: Laboratory of Translational Physiology, Health Sciences Center, Federal University of Espirito Santo, Vitoria, Brazil.|Pharmaceutical Sciences Graduate Program, Vila Velha University (UVV), Vila Velha, ES, Brazil.
authors.forename: Elisardo C
authors.initials: EC
authors.lastname: Vasquez
authors.affiliation: Pharmaceutical Sciences Graduate Program, Vila Velha University (UVV), Vila Velha, ES, Brazil.
authors.forename: Bianca P
authors.initials: BP
authors.lastname: Campagnaro
authors.affiliation: Laboratory of Translational Physiology, Health Sciences Center, Federal University of Espirito Santo, Vitoria, Brazil. meyrelle.vix@terra.com.br.
authors.forename: Silvana S
authors.initials: SS
authors.lastname: Meyrelles
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics* / Q000378:metabolism; D050197:Atherosclerosis / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology; D001854:Bone Marrow Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002784:Cholesterol / Q000097:blood; D042822:Genomic Instability / Q000187:drug effects; D008297:Male; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D015162:Micronucleus Tests; D018384:Oxidative Stress / Q000187:drug effects; D020011:Protective Agents / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D000068677:Sildenafil Citrate / Q000494:pharmacology*; D014280:Triglycerides / Q000097:blood
chemical_list: D001057:Apolipoproteins E; D020011:Protective Agents; D017382:Reactive Oxygen Species; D014280:Triglycerides; D002784:Cholesterol; D000068677:Sildenafil Citrate
keywords: Atherosclerosis; DNA; Genotoxicity; Micronucleus; ROS