Dexamethasone induces apoptosis in pulmonary arterial smooth muscle cells

Dexamethasone suppressed inflammation and haemodynamic changes in an animal model of pulmonary arterial hypertension (PAH). A major target for dexamethasone actions is NF-κB, which is activated in pulmonary vascular cells and perivascular inflammatory cells in PAH. Reverse remodelling is an importan...

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Published in:	Respiratory research 2015-09, Vol.16 (1), p.114, Article 114
Main Authors:	Price, Laura C, Shao, Dongmin, Meng, Chao, Perros, Frederic, Garfield, Benjamin E, Zhu, Jie, Montani, David, Dorfmuller, Peter, Humbert, Marc, Adcock, Ian M, Wort, Stephen J
Format:	Article
Language:	eng
Subjects:	Analysis Animals Anti-Inflammatory Agents - pharmacology Apoptosis Apoptosis - drug effects Care and treatment Caspase 3 - metabolism Cells, Cultured Complications and side effects Cytokines - metabolism Dexamethasone - pharmacology Disease Models, Animal Dose-Response Relationship, Drug Health aspects Humans Hypertension, Pulmonary - chemically induced Hypertension, Pulmonary - drug therapy Hypertension, Pulmonary - metabolism Hypertension, Pulmonary - pathology I-kappa B Proteins - metabolism Inflammation Inflammation Mediators - metabolism Male Monocrotaline Muscle, Smooth, Vascular - drug effects Muscle, Smooth, Vascular - metabolism Muscle, Smooth, Vascular - pathology Myocytes, Smooth Muscle - drug effects Myocytes, Smooth Muscle - metabolism Myocytes, Smooth Muscle - pathology Phosphorylation Pulmonary Artery - drug effects Pulmonary Artery - metabolism Pulmonary Artery - pathology Pulmonary hypertension Rats Rats, Wistar Risk factors Signal Transduction - drug effects Steroids Transcription Factor RelA - metabolism Vascular Remodeling - drug effects
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Summary:	Dexamethasone suppressed inflammation and haemodynamic changes in an animal model of pulmonary arterial hypertension (PAH). A major target for dexamethasone actions is NF-κB, which is activated in pulmonary vascular cells and perivascular inflammatory cells in PAH. Reverse remodelling is an important concept in PAH disease therapy, and further to its anti-proliferative effects, we sought to explore whether dexamethasone augments pulmonary arterial smooth muscle cell (PASMC) apoptosis. Analysis of apoptosis markers (caspase 3, in-situ DNA fragmentation) and NF-κB (p65 and phospho-IKK-α/β) activation was performed on lung tissue from rats with monocrotaline (MCT)-induced pulmonary hypertension (PH), before and after day 14-28 treatment with dexamethasone (5 mg/kg/day). PASMC were cultured from this rat PH model and from normal human lung following lung cancer surgery. Following stimulation with TNF-α (10 ng/ml), the effects of dexamethasone (10(-8)-10(-6) M) and IKK2 (NF-κB) inhibition (AS602868, 0-3 μM (0-3×10(-6) M) on IL-6 and CXCL8 release and apoptosis was determined by ELISA and by Hoechst staining. NF-κB activation was measured by TransAm assay. Dexamethasone treatment of rats with MCT-induced PH in vivo led to PASMC apoptosis as displayed by increased caspase 3 expression and DNA fragmentation. A similar effect was seen in vitro using TNF-α-simulated human and rat PASMC following both dexamethasone and IKK2 inhibition. Increased apoptosis was associated with a reduction in NF-κB activation and in IL-6 and CXCL8 release from PASMC. Dexamethasone exerted reverse-remodelling effects by augmenting apoptosis and reversing inflammation in PASMC possibly via inhibition of NF-κB. Future PAH therapies may involve targeting these important inflammatory pathways.
ISSN:	1465-993X 1465-9921 1465-993X