The PPARγ ligand rosiglitazone attenuates hypoxia-induced endothelin signaling in vitro and in vivo

• Published in: American journal of physiology. Lung cellular and molecular physiology 2011-12, Vol.301 (6), p.L881-L891
• Main Authors: Kang, Bum-Yong, Kleinhenz, Jennifer M, Murphy, Tamara C, Hart, C Michael
• Format: Article
• Language: English
• Subjects: Animals; Aspartic Acid Endopeptidases - genetics; Aspartic Acid Endopeptidases - metabolism; Cell Hypoxia; Cell Proliferation - drug effects; Endothelial Cells - metabolism; Endothelin-1 - genetics; Endothelin-1 - metabolism; Endothelin-Converting Enzymes; Gene Expression; Gene Expression Regulation - drug effects; Humans; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit - genetics; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Lung - metabolism; Lung - pathology; Male; Metalloendopeptidases - genetics; Metalloendopeptidases - metabolism; Mice; Mice, Inbred C57BL; NF-kappa B - genetics; NF-kappa B - metabolism; PPAR gamma - agonists; Pulmonary Artery - pathology; Receptor, Endothelin A - genetics; Receptor, Endothelin A - metabolism; Receptor, Endothelin B - genetics; Receptor, Endothelin B - metabolism; Signal Transduction; Thiazolidinediones - pharmacology
• ISSN: 1040-0605; 1522-1504
• DOI: 10.1152/ajplung.00195.2011

Peroxisome proliferator-activated receptor (PPAR) γ activation attenuates hypoxia-induced pulmonary hypertension (PH) in mice. The current study examined the hypothesis that PPARγ attenuates hypoxia-induced endothelin-1 (ET-1) signaling to mediate these therapeutic effects. To test this hypothesis, human pulmonary artery endothelial cells (HPAECs) were exposed to normoxia or hypoxia (1% O(2)) for 72 h and treated with or without the PPARγ ligand rosiglitazone (RSG, 10 μM) during the final 24 h of exposure. HPAEC proliferation was measured with MTT assays or cell counting, and mRNA and protein levels of ET-1 signaling components were determined. To explore the role of hypoxia-activated transcription factors, selected HPAECs were treated with inhibitors of hypoxia-inducible factor (HIF)-1α (chetomin) or nuclear factor (NF)-κB (caffeic acid phenethyl ester, CAPE). In parallel studies, male C57BL/6 mice were exposed to normoxia (21% O(2)) or hypoxia (10% O(2)) for 3 wk with or without gavage with RSG (10 mg·kg(-1)·day(-1)) for the final 10 days of exposure. Hypoxia increased ET-1, endothelin-converting enzyme-1, and endothelin receptor A and B levels in mouse lung and in HPAECs and increased HPAEC proliferation. Treatment with RSG attenuated hypoxia-induced activation of HIF-1α, NF-κB activation, and ET-1 signaling pathway components. Similarly, treatment with chetomin or CAPE prevented hypoxia-induced increases in HPAEC ET-1 mRNA and protein levels. These findings indicate that PPARγ activation attenuates a program of hypoxia-induced ET-1 signaling by inhibiting activation of hypoxia-responsive transcription factors. Targeting PPARγ represents a novel therapeutic strategy to inhibit enhanced ET-1 signaling in PH pathogenesis.