title: Sildenafil ameliorates biomarkers of genotoxicity in an experimental model of spontaneous atherosclerosis.
abstract: BACKGROUND
  It is well known that enhanced production of reactive oxygen species (ROS) leads to oxidative stress observed in atherosclerosis and that ROS can also cause damage in cellular macromolecules, including DNA. Considering previous report that sildenafil, an inhibitor of phosphodiesterase 5 (PDE5), has antioxidant effects, in the present study we evaluated the effect of this drug on genotoxicity of blood mononuclear cells (MNC) and liver cells from atherosclerotic apolipoprotein E knockout mice (apoE(-/-)).
  
  
  METHODS
  ROS production in MNC was evaluated by flow cytometry with the fluorescent dye dihydroethidium (DHE), a method that has been used to quantify the production of superoxide anion, and DNA damage was evaluated in both MNC and liver cells using the alkaline comet assay. Sildenafil-administered apoE(-/-) mice were compared with strain-matched mice administered with vehicle and with C57BL/6 wild-type (WT) mice.
  
  
  RESULTS
  MNC from apoE(-/-) vehicle exhibited a 2-fold increase in production of superoxide anion in comparison with WT. In contrast, sildenafil-administered apoE(-/-) mice showed superoxide anion levels similar to those observed in WT mice. Similarly, MNC and liver cells from apoE(-/-) vehicle mice showed a 4-fold and 2-fold augmented DNA fragmentation compared with WT, respectively, and sildenafil-administered apoE(-/-) mice exhibited minimal DNA damage in those cells similar to WT mice.
  
  
  CONCLUSIONS
  ApoE(-/-) mice chronically administered with sildenafil exhibited reduced levels of superoxide anion in MNC and less DNA fragmentation in MNC and liver cells, which are biomarkers of genotoxicity. Therefore, sildenafil may offer a new perspective to the use of PDE5 inhibitors to protect against DNA damage, in cells involved in the inflammatory and dyslipidemic processes that accompany atherosclerosis.
authors: Laboratory of Translational Physiology, Health Sciences Center, Federal University of Espirito Santo (UFES), Vitoria, Brazil. evasquez@pq.cnpq.br.
authors: Bianca P
authors: BP
authors: Rodrigues
authors: Bianca P
authors: BP
authors: Campagnaro
authors: Camille M
authors: CM
authors: Balarini
authors: Thiago M C
authors: TM
authors: Pereira
authors: Silvana S
authors: SS
authors: Meyrelles
authors: Elisardo C
authors: EC
authors: Vasquez
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics*; D050197:Atherosclerosis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D020552:Comet Assay; D053938:DNA Fragmentation / Q000187:drug effects; D004195:Disease Models, Animal; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008074:Lipoproteins / Q000097:blood; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018384:Oxidative Stress / Q000187:drug effects; D058986:Phosphodiesterase 5 Inhibitors / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D011687:Purines / Q000494:pharmacology; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000494:pharmacology*; D013481:Superoxides / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014280:Triglycerides / Q000097:blood
chemical_list: D001057:Apolipoproteins E; D008074:Lipoproteins; D058986:Phosphodiesterase 5 Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D014280:Triglycerides; D013481:Superoxides; D000068677:Sildenafil Citrate
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