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Increased expression of the cGMP‐inhibited cAMP‐specific (PDE3) and cGMP binding cGMP‐specific (PDE5) phosphodiesterases in models of pulmonary hypertension
Author(s) -
Murray Fiona,
MacLean Margaret R,
Pyne Nigel J
Publication year - 2002
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0704984
Subject(s) - phosphodiesterase 3 , pde10a , phosphodiesterase , pulmonary hypertension , hypoxia (environmental) , protein kinase a , endocrinology , medicine , cgmp specific phosphodiesterase type 5 , biology , pulmonary artery , vascular smooth muscle , pharmacology , kinase , chemistry , microbiology and biotechnology , biochemistry , enzyme , sildenafil , smooth muscle , organic chemistry , oxygen
Chronic hypoxic treatment of rats (to induce pulmonary hypertension, PHT) for 14 days increased cGMP‐inhibited cAMP specific phosphodiesterase (PDE3) and cGMP binding cGMP specific phosphodiesterase (PDE5) activities in pulmonary arteries. The objective of this study was to establish the molecular basis for these changes in both animal and cell models of PHT. In this regard, RT–PCR and quantitative Western blotting analysis was applied to rat pulmonary artery homogenates and human pulmonary ‘artery’ smooth muscle cell (HPASMC) lysates. PDE3A/B gene transcript levels were increased in the main, first, intrapulmonary and resistance pulmonary arteries by chronic hypoxia. mRNA transcript and protein levels of PDE5A2 in the main and first branch pulmonary arteries were also increased by chronic hypoxia, with no effect on PDE5A1/A2 in the intra‐pulmonary and resistance vessels. The expression of PDE3A was increased in HPASMCs maintained under chronic hypoxic conditions for 14 days. This may be mediated via a protein kinase A‐dependent mechanism, as treatment of cells with Br‐cAMP (100 μ M ) mimicked chronic hypoxia in increasing PDE3A expression, while the PKA inhibitor, H8 peptide (50 μ M ) abolished the hypoxic‐dependent increase in PDE3A transcript. We also found that the treatment of HPASMCs with the inhibitor of κB degradation Tosyl‐Leucyl‐Chloro‐Ketone (TLCK, 50 μ M ) reduced PDE5 transcript levels, suggesting a role for this transcription factor in the regulation of PDE5 gene expression. Our results show that increased expression of PDE3 and PDE5 might explain some changes in vascular reactivity of pulmonary vessels from rats with PHT. We also report that NF‐κB might regulate basal PDE5 expression.British Journal of Pharmacology (2002) 137 , 1187–1194. doi: 10.1038/sj.bjp.0704984