The PPARγ ligand, RSG, attenuates decreases in HUWE1 and miR-98 levels and increases in p65 and ET-1 levels in SS mouse lung and in HEM-treated HPAECs. (A) RVSP was recorded in anesthetized mice with a pressure transducer. Each bar represents the mean RVSP in mm Hg ± SEM; n = 5 to 6. (B) The ratio of the weight of the RV to the LV + septum [RV: (LV + S)] is presented as an index of RVH. n = 5 to 6. (C-F) Whole lung homogenates were collected from (AA) and SS mice following gavage with RSG (10 mg/kg per day) or vehicle for 10 days. Real-time qPCR was performed on lung tissue. Lung HUWE1 (C), miR-98 (D), p65 (E), or ET-1 (F) levels are expressed relative to GAPDH or RNU6B and normalized to CON values. Each bar represents the mean ± SEM. *P < .05 vs AA; ⁺P < .05 vs SS, n = 5 to 6. (G-J) HPAECs were treated with HEM (5 µM) for 72 hours. During the final 24 hours of HEM exposure, selected HPAECs were treated ± RSG (10 μM). Real-time qPCR was performed for HUWE1 (G), miR-98 (H), p65 (I), or ET-1 (J) levels. Each bar represents the mean ± SEM relative to RNU6B or GAPDH as indicated. *P < .05 vs HEM/RSG(−), n = 3 to 6. (K) Hypothetical schema defining the role of PPARγ/HUWE1/miR-98 signaling in SCD-PH pathogenesis. Hemolysis induces reductions in PPARγ that decrease miR-98 and HUWE1 levels. Reductions in miR-98 stimulate ET-1 and reductions in HUWE1 increase NF-κB, adhesion molecule expression, and endothelial dysfunction promoting SCD-PH pathogenesis.