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MicroRNA‐27a and PPARγ regulate endothelin signaling in sickle cell disease‐related pulmonary hypertension
Author(s) -
Kang Bum-Yong,
Park Kathy K.,
Tan Fang,
Sutliff Roy L.,
Ofori-Acquah Solomon F.,
Hart C. Michael
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.873.2
Subject(s) - rosiglitazone , gene knockdown , hypoxia (environmental) , pulmonary hypertension , endothelin 1 , peroxisome proliferator activated receptor , downregulation and upregulation , pathogenesis , medicine , endocrinology , microrna , cancer research , apoptosis , biology , chemistry , receptor , gene , biochemistry , organic chemistry , oxygen
Pulmonary hypertension (PH) is a serious complication of sickle cell disease (SCD) that causes significant morbidity and mortality. The PPARγ ligand rosiglitazone (RSG) attenuates hypoxia‐induced PH and endothelin (ET)‐1 levels. To examine these pathways in SCD, we hypothesized that increased levels of microRNA (miR)‐ 27a reduce PPARγ expression to increase ET‐1 levels and PH. Our results demonstrate that levels of miR‐27a, NF‐κB, and ET‐1 were increased in the lungs of 8–10 week old SCD transgenic mice compared to controls whereas PPARγ levels were reduced. In parallel studies, C57BL/6 mice were exposed to control or hypoxic (10% O 2 ) conditions for 3‐weeks ±RSG (10 mg/kg/d) for the final 10 d of exposure. RSG attenuated hypoxia‐induced increases in miR‐27a in C57BL/6 mouse lung. Human pulmonary artery endothelial cells (HPAECs) were exposed to control (21% O 2 ) or hypoxic (1% O 2 ) conditions for 72 h. Hypoxia increased HPAEC proliferation, miR‐27a, NF‐κB, and ET‐1 expression, and reduced PPARγ levels. These alterations were attenuated by treatment with RSG (10 μM). In contrast, overexpression of miR‐27a or knockdown of PPARγ increased HPAEC proliferation. Collectively, these findings suggest that miR‐27a and PPARγ regulate ET‐1 signaling and that targeting PPARγ may represent a novel therapeutic approach in SCD‐PH pathogenesis. Atlanta VAMC, NIH DK074519 /HL102167, Emory/Children Healthcare CEB F16788 ‐00 .