Increased expression of the cGMP-inhibited cAMP-specific (PDE3) and cGMP binding cGMP-specific (PDE5) phosphodiesterases in models of pulmonary hypertension

Murray, F., MacLean, M.R. and Pyne, N.J. (2002) Increased expression of the cGMP-inhibited cAMP-specific (PDE3) and cGMP binding cGMP-specific (PDE5) phosphodiesterases in models of pulmonary hypertension. British Journal of Pharmacology, 137(8), pp. 1187-1194. (doi: 10.1038/sj.bjp.0704984)

Full text not currently available from Enlighten.

Abstract

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 μM) mimicked chronic hypoxia in increasing PDE3A expression, while the PKA inhibitor, H8 peptide (50 μM) 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 μM) 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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:MacLean, Professor Margaret
Authors: Murray, F., MacLean, M.R., and Pyne, N.J.
College/School:College of Medical Veterinary and Life Sciences
College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
Journal Name:British Journal of Pharmacology
Publisher:0007-1188
ISSN (Online):1476-5381
Published Online:27 November 2002

University Staff: Request a correction | Enlighten Editors: Update this record