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The PPARγ Ligand, Rosiglitazone Attenuates Hypoxia‐Induced Endothelin Signaling in vitro and in vivo
Author(s) -
Kang BumYong,
Ritzenthaler Jeff D.,
Hart Michael C.
Publication year - 2011
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.25.1_supplement.861.7
Subject(s) - rosiglitazone , hypoxia (environmental) , endothelin 1 , in vivo , peroxisome proliferator activated receptor , chemistry , pharmacology , endothelin receptor , endocrinology , receptor , medicine , biology , oxygen , microbiology and biotechnology , organic chemistry
PPARγ activation attenuated hypoxia‐induced pulmonary hypertension (PH) in mice although the mechanisms for these effects remain to be completely defined. We hypothesized that PPARγ attenuates hypoxia‐induced endothelin‐1 (ET‐1) signaling. Human pulmonary artery endothelial cells (HPAECs) were exposed to hypoxia (1% O2) or normoxia for 72 h and treated ± rosiglitazone (RSG, 10 μM) during the last 24 h. Male C57BL/6 mice were exposed to hypoxia (10% O2) or normoxia (21% O2) for 3 wk ± gavage with RSG (10 mg/kg/d) for the final 10 d of exposure. Selected HPAECs were treated with chetomin (HIF‐1α inhibitor, 25 nM) or with CAPE (NF‐κB inhibitor, 20 μM) for 3 h. HPAEC proliferation was measured with MTT assays. Our findings demonstrate that hypoxia increased ET‐1, endothelin converting enzyme‐1, endothelin receptor A and B levels in mouse lung and in HPAECs and increased HPAEC proliferation. Treatment with RSG attenuated these hypoxia‐induced increases. Hypoxia‐induced increases in HIF‐1α and NF‐κB nuclear binding were attenuated by RSG. Treatment with chetomin or CAPE also prevented hypoxia‐induced increases in ET‐1 mRNA levels. These findings suggest that PPARγ attenuates hypoxia‐induced ET‐1 signaling by inhibiting activation of hypoxia‐responsive transcription factors. Targeting PPARγ represents a novel therapeutic strategy to inhibit ET‐1 signaling that contributes to PH pathogenesis.