title: Differential effects of organic nitrates on endothelial progenitor cells are determined by oxidative stress.
abstract: OBJECTIVE
  Reduced levels and impaired function of endothelial progenitor cells (EPCs) foster development and progression of atherosclerotic lesions. Endothelial nitric oxide synthase (eNOS)-derived NO regulates EPC mobilization and function. Organic nitrates release NO, and therefore may favorably affect EPC biology.
  
  
  RESULTS
  We compared the effects of 2 different nitrates on circulating EPC numbers and function. Treatment of rats with pentaerythritol-trinitrate (PETriN) or isosorbide dinitrate (ISDN) increased circulating EPC levels. EPC from ISDN- but not PETriN-treated animals displayed impaired migratory capacity and increased reactive oxygen species formation in EPCs. In vitro treatment with ISDN reduced migration and incorporation of human EPCs into vascular structures on matrigel, whereas PETriN improved EPC function. ISDN, but not PETriN, increased NADPH oxidase-mediated oxidative stress in cultured human EPCs. Addition of polyethylene-glycolated superoxide dismutase or diphenyliodonium normalized both ISDN-induced superoxide anion production and impaired migratory capacity of EPCs.
  
  
  CONCLUSIONS
  Long-acting nitrates increase levels of circulating EPCs, but differ in their effects on EPC function dependent on the induction of intracellular oxidative stress. Organic nitrates that improve EPC function may confer long-term cardiovascular protection based on their beneficial effects on EPC biology.
authors.affiliation: Department of Cardiology, University of Würzburg, University Hospital, Würzburg, Germany. Thum_T@klinik.uni-wuerzburg.de
authors.forename: Thomas
authors.initials: T
authors.lastname: Thum
authors.forename: Daniela
authors.initials: D
authors.lastname: Fraccarollo
authors.forename: Sabrina
authors.initials: S
authors.lastname: Thum
authors.forename: Maximilian
authors.initials: M
authors.lastname: Schultheiss
authors.forename: Andreas
authors.initials: A
authors.lastname: Daiber
authors.forename: Philip
authors.initials: P
authors.lastname: Wenzel
authors.forename: Thomas
authors.initials: T
authors.lastname: Munzel
authors.forename: Georg
authors.initials: G
authors.lastname: Ertl
authors.forename: Johann
authors.initials: J
authors.lastname: Bauersachs
mesh_terms: D000818:Animals; D001773:Blood Cells / Q000187:drug effects; D001853:Bone Marrow / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D006801:Humans; D007548:Isosorbide Dinitrate / Q000494:pharmacology*; D008297:Male; D009249:NADP / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects; D010417:Pentaerythritol Tetranitrate / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D013234:Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D013481:Superoxides / Q000378:metabolism
chemical_list: D020030:Nitric Oxide Donors; D017382:Reactive Oxygen Species; D010417:Pentaerythritol Tetranitrate; D013481:Superoxides; C100210:pentrinitrol; D009249:NADP; D007548:Isosorbide Dinitrate