Rosiglitazone preserves pulmonary vascular function in lambs with increased pulmonary blood flow

Background:Pulmonary vascular function is impaired with increased pulmonary blood flow (PBF). We hypothesized that a peroxisome proliferator–activated receptor-? (PPAR-?) agonist would mitigate this effect.Methods:An aorta-to-pulmonary-artery shunt was placed in 11 fetal lambs. Lambs received the PPAR-? 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-? protein expression was lower in vehicle-treated shunt lambs than in normal and RG-treated shunt lambs.Conclusion:The PPAR-? 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.