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Hemin‐Induced miR‐27a Reduces PPARγ Expression in Sickle Cell Disease with Pulmonary Hypertension
Author(s) -
Kang BumYong,
Park Kathy K,
Tan Fang,
Ghosh Samit,
Sutliff Roy L.,
OforiAcquah Solomon F.,
Hart C. Michael
Publication year - 2013
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.27.1_supplement.724.2
Subject(s) - hemin , nox4 , rosiglitazone , oxidative stress , endocrinology , medicine , hemolysis , peroxisome proliferator activated receptor , apoptosis , receptor , chemistry , nadph oxidase , heme , biochemistry , enzyme
The hallmark of sickle cell disease (SCD) is hemolysis, vaso‐occlusion, and oxidative stress. Pulmonary hypertension (PH) is a serious complication of SCD that causes significant morbidity and mortality. We previously demonstrated that: 1) activation of the nuclear hormone receptor, peroxisome proliferator‐activated receptor gamma (PPARγ attenuated hypoxia‐induced Nox4 and endothelin‐1 (ET‐1) expression and PH in mice and 2) that levels of Nox4 and ET‐1 were increased in the lungs of 8–10 week old SCD transgenic mice compared to controls whereas PPARγ levels were reduced. The current study further examines mechanisms of PH in SCD. Human pulmonary arterial endothelial cells (HPAECs) were treated with the hemolysis product, hemin (5 μM), for 72 h. Hemin reduced PPARγ and increased Nox4 and ET‐1 expression and HPAEC proliferation. MicroRNA‐27a (miR‐27a), which negatively regulates PPARγ, was increased in hemin‐treated HPAECs. In contrast, treating HPAECs with the PPARγ rosiglitazone (10 μM) for the final 24 h of hemin exposure attenuated increased HPAEC proliferation and miR‐27a levels. These findings suggest that hemin increases miR‐27a to reduce PPARγ and increase Nox4, ET‐1, and PAEC proliferation. These results suggest novel pathways for SCD‐PH pathogenesis and therapy. Supported by Atlanta VA Merit Review, NIH HL102167 , and Emory/Childrens Healthcare CEB F16788–00.