Peroxisome Proliferator-Activated Receptor γ 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.
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 γ (PPARγ) 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 PPARγ 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 PPARγ 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 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 attenuate SCD-PH pathogenesis.
1 Department of Medicine, Atlanta Veterans Affairs and Emory University Medical Centers, Atlanta, Georgia; and.
Bum-Yong
0000-0001-8251-1637
BY
Kang
1 Department of Medicine, Atlanta Veterans Affairs and Emory University Medical Centers, Atlanta, Georgia; and.
Kathy
K
Park
1 Department of Medicine, Atlanta Veterans Affairs and Emory University Medical Centers, Atlanta, Georgia; and.
Jennifer M
JM
Kleinhenz
1 Department of Medicine, Atlanta Veterans Affairs and Emory University Medical Centers, Atlanta, Georgia; and.
Tamara C
TC
Murphy
1 Department of Medicine, Atlanta Veterans Affairs and Emory University Medical Centers, Atlanta, Georgia; and.
Roy L
RL
Sutliff
2 Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia.
David
D
Archer
1 Department of Medicine, Atlanta Veterans Affairs and Emory University Medical Centers, Atlanta, Georgia; and.
C Michael
CM
Hart
D000755:Anemia, Sickle Cell / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D019332:Endothelin-1 / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D006427:Hemin / Q000494:pharmacology; D006801:Humans; D006976:Hypertension, Pulmonary / Q000150:complications / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D017380:Hypertrophy, Right Ventricular / Q000150:complications / Q000235:genetics / Q000503:physiopathology; D008024:Ligands; D008168:Lung / Q000473:pathology*; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism*; D008954:Models, Biological; D047495:PPAR gamma / Q000378:metabolism*; D050784:Proto-Oncogene Protein c-ets-1 / Q000378:metabolism*; D011651:Pulmonary Artery / Q000473:pathology; D000077154:Rosiglitazone; D013599:Systole / Q000187:drug effects; D045162:Thiazolidinediones / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects
C494041:ETS1 protein, human; D019332:Endothelin-1; C494042:Ets1 protein, mouse; D008024:Ligands; C531388:MIRN27 microRNA, human; D035683:MicroRNAs; C540674:Mirn27 microRNA, mouse; D047495:PPAR gamma; D050784:Proto-Oncogene Protein c-ets-1; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D006427:Hemin
microRNA-27a; peroxisome proliferator-activated receptor γ; pulmonary hypertension; sickle cell disease; v-ets avian erythroblastosis virus E26 oncogene homolog 1