title: Oxidant stress impairs in vivo reendothelialization capacity of endothelial progenitor cells from patients with type 2 diabetes mellitus: restoration by the peroxisome proliferator-activated receptor-gamma agonist rosiglitazone.
abstract: BACKGROUND
  Endothelial progenitor cells (EPCs) are thought to contribute to endothelial recovery after arterial injury. We therefore compared in vivo reendothelialization capacity of EPCs derived from patients with diabetes mellitus and healthy subjects. Moreover, we examined the effect of treatment with the peroxisome proliferator-activated receptor-gamma agonist rosiglitazone on oxidant stress, nitric oxide (NO) bioavailability, and the in vivo reendothelialization capacity of EPCs from diabetic individuals.
  
  
  RESULTS
  In vivo reendothelialization capacity of EPCs from diabetic patients (n=30) and healthy subjects (n=10) was examined in a nude mouse carotid injury model. Superoxide and NO production of EPCs was determined by electron spin resonance spectroscopy. Thirty patients with diabetes mellitus were randomized to 2 weeks of rosiglitazone (4 mg BID p.o.) or placebo treatment. In vivo reendothelialization capacity of EPCs derived from diabetic subjects was severely reduced compared with EPCs from healthy subjects (reendothelialized area: 8+/-3% versus 37+/-10%; P<0.001). EPCs from diabetic individuals had a substantially increased superoxide production and impaired NO bioavailability. Small-interfering RNA silencing of NAD(P)H oxidase subunit p47(phox) reduced superoxide production and restored NO bioavailability and in vivo reendothelialization capacity of EPCs from diabetic patients. Importantly, rosiglitazone therapy normalized NAD(P)H oxidase activity, restored NO bioavailability, and improved in vivo reendothelialization capacity of EPCs from diabetic patients (reendothelialized area: placebo versus rosiglitazone, 8+/-1% versus 38+/-5%; P<0.001).
  
  
  CONCLUSIONS
  In vivo reendothelialization capacity of EPCs derived from individuals with diabetes mellitus is severely impaired at least partially as a result of increased NAD(P)H oxidase-dependent superoxide production and subsequently reduced NO bioavailability. Rosiglitazone therapy reduces NAD(P)H oxidase activity and improves reendothelialization capacity of EPCs from diabetic individuals, representing a potential novel mechanism whereby peroxisome proliferator-activated receptor-gamma agonism promotes vascular repair.
authors.affiliation: Abteilung Kardiologie und Angiologie, Medizinische Hochschule Hannover, Hannover, Germany.
authors.forename: Sajoscha A
authors.initials: SA
authors.lastname: Sorrentino
authors.forename: Ferdinand H
authors.initials: FH
authors.lastname: Bahlmann
authors.forename: Christian
authors.initials: C
authors.lastname: Besler
authors.forename: Maja
authors.initials: M
authors.lastname: Müller
authors.forename: Svenja
authors.initials: S
authors.lastname: Schulz
authors.forename: Nina
authors.initials: N
authors.lastname: Kirchhoff
authors.forename: Carola
authors.initials: C
authors.lastname: Doerries
authors.forename: Tibor
authors.initials: T
authors.lastname: Horváth
authors.forename: Anne
authors.initials: A
authors.lastname: Limbourg
authors.forename: Florian
authors.initials: F
authors.lastname: Limbourg
authors.forename: Danilo
authors.initials: D
authors.lastname: Fliser
authors.forename: Hermann
authors.initials: H
authors.lastname: Haller
authors.forename: Helmut
authors.initials: H
authors.lastname: Drexler
authors.forename: Ulf
authors.initials: U
authors.lastname: Landmesser
mesh_terms: D000368:Aged; D000818:Animals; D001794:Blood Pressure; D002339:Carotid Arteries; D002784:Cholesterol / Q000097:blood; D003924:Diabetes Mellitus, Type 2 / Q000503:physiopathology*; D003925:Diabetic Angiopathies / Q000188:drug therapy* / Q000503:physiopathology*; D042783:Endothelial Cells / Q000473:pathology / Q000502:physiology*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000503:physiopathology*; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D008954:Models, Biological; D009569:Nitric Oxide / Q000502:physiology; D018384:Oxidative Stress; D047495:PPAR gamma / Q000819:agonists*; D012016:Reference Values; D000077154:Rosiglitazone; D013234:Stem Cells / Q000473:pathology / Q000502:physiology; D013481:Superoxides / Q000378:metabolism; D045162:Thiazolidinediones / Q000627:therapeutic use*; D014665:Vasodilator Agents / Q000627:therapeutic use*
chemical_list: D047495:PPAR gamma; D045162:Thiazolidinediones; D014665:Vasodilator Agents; D000077154:Rosiglitazone; D013481:Superoxides; D009569:Nitric Oxide; D002784:Cholesterol