title: Rosiglitazone preserves pulmonary vascular function in lambs with increased pulmonary blood flow.
abstract: BACKGROUND
  Pulmonary vascular function is impaired with increased pulmonary blood flow (PBF). We hypothesized that a peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist would mitigate this effect.
  
  
  METHODS
  An aorta-to-pulmonary-artery shunt was placed in 11 fetal lambs. Lambs received the PPAR-γ agonist rosiglitazone (RG, 3 mg/kg/d, n = 6) or vehicle (n = 5) for 4 wk. Lung tissue from five normal 4-wk-old lambs was used for comparisons.
  
  
  RESULTS
  At 4 wk, pulmonary artery pressure (PAP) and vascular resistance (PVR) decreased with inhaled nitric oxide (NO) in RG- and vehicle-treated shunt lambs. PAP and PVR decreased with acetylcholine (Ach) in RG-treated, but not vehicle-treated, shunt lambs. In vehicle-treated shunt lambs, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity, rac1, superoxide, and 3-nitrotyrosine (3-NT) levels were increased, and Ser1177 endothelial NO synthase (eNOS) protein was decreased as compared with normal lambs. In RG-treated shunt lambs, NOx, Ser1177 eNOS protein, and eNOS activity were increased, and NADPH activity, rac1, superoxide levels, and 3-NT levels were decreased, as compared with vehicle-treated shunt lambs. PPAR-γ protein expression was lower in vehicle-treated shunt lambs than in normal and RG-treated shunt lambs.
  
  
  CONCLUSIONS
  The PPAR-γ agonist RG prevents the loss of agonist-induced endothelium-dependent pulmonary vascular relaxation in lambs with increased PBF, in part, due to decreased oxidative stress and/or increased NO production.
authors.affiliation: Department of Pediatrics, University of California, San Francisco, San Francisco, CA, USA. oiship@peds.ucsf.edu
authors.forename: Peter E
authors.initials: PE
authors.lastname: Oishi
authors.forename: Shruti
authors.initials: S
authors.lastname: Sharma
authors.forename: Sanjeev A
authors.initials: SA
authors.lastname: Datar
authors.forename: Sanjiv
authors.initials: S
authors.lastname: Kumar
authors.forename: Saurabh
authors.initials: S
authors.lastname: Aggarwal
authors.forename: Qing
authors.initials: Q
authors.lastname: Lu
authors.forename: Gary
authors.initials: G
authors.lastname: Raff
authors.forename: Anthony
authors.initials: A
authors.lastname: Azakie
authors.forename: Jong-Hau
authors.initials: JH
authors.lastname: Hsu
authors.forename: Eniko
authors.initials: E
authors.lastname: Sajti
authors.forename: Sohrab
authors.initials: S
authors.lastname: Fratz
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Black
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Fineman
mesh_terms: D000109:Acetylcholine / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western; D006439:Hemodynamics; D019255:NADPH Oxidases / Q000378:metabolism; D009569:Nitric Oxide / Q000008:administration & dosage / Q000494:pharmacology; D047495:PPAR gamma / Q000819:agonists* / Q000378:metabolism; D011652:Pulmonary Circulation / Q000187:drug effects* / Q000502:physiology*; D011669:Pulmonary Wedge Pressure / Q000187:drug effects / Q000502:physiology; D000077154:Rosiglitazone; D012756:Sheep; D013482:Superoxide Dismutase / Q000378:metabolism; D045162:Thiazolidinediones / Q000494:pharmacology*; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism; D014655:Vascular Resistance / Q000187:drug effects / Q000502:physiology; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
chemical_list: D047495:PPAR gamma; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D009569:Nitric Oxide; C002744:3-nitrotyrosine; D014443:Tyrosine; D013482:Superoxide Dismutase; D019255:NADPH Oxidases; D020830:rac1 GTP-Binding Protein; D000109:Acetylcholine