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Hypoxia downregulates peroxisome proliferator‐activated receptor‐gamma in human pulmonary artery smooth muscle cells by NF‐κB and ERK1/2
Author(s) -
Lu Xianghuai,
Ramirez Allan,
Nanes Mark,
Hart C. Michael
Publication year - 2010
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.24.1_supplement.796.9
Subject(s) - peroxisome proliferator activated receptor , hypoxia (environmental) , receptor , transcription factor , rosiglitazone , chemistry , in vivo , biology , microbiology and biotechnology , endocrinology , medicine , pharmacology , biochemistry , organic chemistry , oxygen , gene
The ligand‐activated transcription factor, peroxisome proliferator‐activated receptor gamma (PPARγ), regulates metabolism, cell proliferation, and inflammation. We have observed that the PPARγ ligand, rosiglitazone, inhibits hypoxia‐induced proliferation of human pulmonary artery smooth muscle cells (HPASMC) in vitro and hypoxia‐induced pulmonary hypertension in mice in vivo . Furthermore, we have reported that in vitro hypoxia exposure reduced PPARγ protein levels in isolated HPASMC and pulmonary artery endothelial cells (Nisbet, 2009). The current study examined the molecular mechanisms involved in hypoxia regulation of PPARγ. Exposure to 1% oxygen for 72 hours decreased PPARγ1 mRNA and protein levels in HPASMC. Compared to control conditions, hypoxia decreased the activity of a PPARγ luciferase reporter (PPRE‐Luc) by roughly 60%. Inhibiting NF‐κB by applying either p65 siRNA or the NF‐κB specific inhibitor, CAPE, attenuated hypoxia‐induced inhibition of PPRE‐Luc activity. Hypoxia‐induced inhibition of PPRE‐Luc activity was also attenuated by treatment with PD98059, a specific inhibitor of ERK1/2. Mammalian two hybrid assays suggested that PPARγ binds to p65. Deletion of the p65 activation domain (amino acids 308‐551) abrogated p65 binding to PPARγ. These findings suggest that hypoxia activates NF‐κB and MAP kinase pathways to reduce PPAR transcription and PPARγ expression in HPASMC.