| First Author | Kang BY | Year | 2017 |
| Journal | Am J Respir Cell Mol Biol | Volume | 56 |
| Issue | 1 | Pages | 131-144 |
| PubMed ID | 27612006 | Mgi Jnum | J:254656 |
| Mgi Id | MGI:6112530 | Doi | 10.1165/rcmb.2016-0166OC |
| Citation | Kang BY, et al. (2017) Peroxisome Proliferator-Activated Receptor gamma Regulates the V-Ets Avian Erythroblastosis Virus E26 Oncogene Homolog 1/microRNA-27a Axis to Reduce Endothelin-1 and Endothelial Dysfunction in the Sickle Cell Mouse Lung. Am J Respir Cell Mol Biol 56(1):131-144 |
| abstractText | Pulmonary hypertension (PH), a serious complication of sickle cell disease (SCD), causes significant morbidity and mortality. Although a recent study determined that hemin release during hemolysis triggers endothelial dysfunction in SCD, the pathogenesis of SCD-PH remains incompletely defined. This study examines peroxisome proliferator-activated receptor gamma (PPARgamma) regulation in SCD-PH and endothelial dysfunction. PH and right ventricular hypertrophy were studied in Townes humanized sickle cell (SS) and littermate control (AA) mice. In parallel studies, SS or AA mice were gavaged with the PPARgamma agonist, rosiglitazone (RSG), 10 mg/kg/day, 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 right ventricular hypertrophy associated with reduced lung levels of PPARgamma and increased levels of microRNA-27a (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 and E selectin). HPAECs treated with hemin had increased ETS1, miR-27a, ET-1, and endothelial dysfunction and decreased PPARgamma levels. These derangements were attenuated by ETS1 knockdown, inhibition of miR-27a, or PPARgamma overexpression. In SS mouse lung or in hemin-treated HPAECs, activation of PPARgamma with RSG attenuated reductions in PPARgamma 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 PPARgamma and increase ET-1 and endothelial dysfunction. PPARgamma activation attenuated SCD-associated signaling derangements, suggesting a novel therapeutic approach to attenuate SCD-PH pathogenesis. |
