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-gamma (PPARγ) agonist would mitigate this effect. METHODS: An aorta to pulmonary artery shunt was placed in 11 fetal lambs. Lambs received the PPARγ agonist rosiglitazone (RG, 3 mg/kg/day, n=6) or vehicle (n=5) for 4-weeks. Lung tissue from 5 normal 4-week lambs was used for comparisons. RESULTS: At 4-weeks, pulmonary artery pressure (PAP) and vascular resistance (PVR) decreased with inhaled NO in RG and vehicle-treated shunt lambs. PAP and PVR decreased with acetylcholine in RG-treated, not vehicle-treated shunt lambs. In vehicle-treated shunt lambs, NADPH oxidase activity, rac1, superoxide, and 3-nitrotyrosine (3-NT) levels were increased and Ser1177 endothelial NO synthase (eNOS) protein was decreased compared to normal lambs. In RG-treated shunt lambs, NO(X), Ser1177 eNOS protein and eNOS activity were increased, and NADPH activity, rac1, superoxide levels and 3-NT levels were decreased, compared to vehicle-treated shunt lambs. PPARγ protein expression was lower in vehicle-treated shunt lambs than normal and RG-treated shunt lambs. CONCLUSIONS: The PPARγ 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.