PPARgamma Antagonists Attenuate Hypoxia‐induced Pulmonary Hypertension

Abstract

Rationale: Peroxisome proliferators‐activated receptor γ (PPARγ) agonists attenuate hypoxia (Hx)‐induced pulmonary artery (PA) remodeling. The present study tested the hypothesis that PPARγ antagonists exacerbate Hx‐induced PA remodeling.Methods: Wistar‐Kyoto rats were randomized to normoxia (Nx) and hypobaric Hx and treated with or without the PPARγ agonist Rosiglitazone (ROSI) or the PPARγ antagonists GW9662, T0070907, or SR‐202 for 3 weeks.Results: PA catheterization performed on Hx‐ROSI treated groups had no attenuation of Hx‐pulmonary hypertension (PH) vs Hx‐Controls. However, PPARγ antagonist treatment resulted in a decrease in PA pressures in response to chronic Hx [p < 0.05]. PA morphometric analysis demonstrated a marked decrease in proximal and distal PA remodeling vs Hx‐Controls [p = 0.003]. Right ventricular hypertrophy [RV/(LV+S)] was decreased in both the Hx‐PPARγ agonist and antagonist treated groups [p = 0.05]. The decrease in PA remodeling and RV hypertrophy was due to inhibition of proliferation without an increase in apoptosis.Conclusions: PPARγ antagonists GW9662, T0070907 and SR‐202 exert a significant vascular protective effect on Hx‐induced PH and PA remodeling.