PPAR γ Regulates the ETS1/miR-27a Axis to Reduce ET-1 and Endothelial Dysfunction in the Sickle Cell Mouse Lung.

This study examines peroxisome proliferator-activated receptor gamma (PPARγ) regulation in SCD-PH and endothelial dysfunction. PH and right ventricular hypertrophy (RVH) were studied in Townes humanized sickle cell (SS) and littermate control (AA) mice. In parallel studies, SS or AA mice were gavaged with the PPARγ agonist, rosiglitazone (RSG, 10 mg/kg/d) or vehicle for 10 days. In vitro, human pulmonary artery endothelial cells (HPAECs) were treated with vehicle or hemin for 72 hours, and selected HPAECs were treated with RSG. SS mice developed PH and RVH associated with reduced lung levels of PPARγ and increased levels of miR-27a, v-ets avian erythroblastosis virus E26 oncogene homolog 1 (ETS1), endothelin-1 (ET-1), and markers of endothelial dysfunction (platelet/endothelial cell adhesion molecule 1, PECAM1 and E selectin, E-SEL). HPAEC treated with hemin had increased ETS1, miR-27a, ET-1, and endothelial dysfunction and decreased PPARγ levels. These derangements were attenuated by ETS1 knockdown, inhibition of miR-27a, or PPARγ overexpression. In SS mouse lung or in hemin-treated HPAECs, activation of PPARγ with RSG attenuated reductions in PPARγ and increases in miR-27a, ET-1, and markers of endothelial dysfunction. In SCD-PH pathogenesis, ETS1 stimulates increases in miR-27a levels that reduce PPARγ and increase ET-1 and endothelial dysfunction. PPARγ activation attenuated SCD-associated signaling derangements suggesting a novel therapeutic approach to attenuat...
Source: Am J Respir Cell Mol... - Category: Respiratory Medicine Authors: Tags: Am J Respir Cell Mol Biol Source Type: research