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

Abstract

1. 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. 2. 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. 3. 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 microM) mimicked chronic hypoxia in increasing PDE3A expression, while the PKA inhibitor, H8 peptide (50 microM) abolished the hypoxic-dependent increase in PDE3A transcript. 4. We also found that the treatment of HPASMCs with the inhibitor of kappaB degradation Tosyl-Leucyl-Chloro-Ketone (TLCK, 50 microM) reduced PDE5 transcript levels, suggesting a role for this transcription factor in the regulation of PDE5 gene expression. 5. 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-kappaB might regulate basal PDE5 expression.

• Authors: Fiona Murray, Margaret R MacLean, Nigel J Pyne
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 137 Issue 8 Pg. 1187-94 (Dec 2002) ISSN: 0007-1188 [Print] England
• PMID: 12466227 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Tosyllysine Chloromethyl Ketone
• Cyclic AMP
• 3',5'-Cyclic-AMP Phosphodiesterases
• Cyclic Nucleotide Phosphodiesterases, Type 3
• PDE3A protein, human
• Pde3a protein, rat
• 3',5'-Cyclic-GMP Phosphodiesterases
• Cyclic Nucleotide Phosphodiesterases, Type 5
• PDE5A protein, human
• Pde5a protein, rat
• Cyclic GMP

Topics

• 3',5'-Cyclic-AMP Phosphodiesterases (antagonists & inhibitors, biosynthesis, genetics, metabolism)
• 3',5'-Cyclic-GMP Phosphodiesterases (antagonists & inhibitors, biosynthesis, genetics, metabolism)
• Animals
• Cell Line
• Cyclic AMP (metabolism, pharmacology)
• Cyclic GMP (metabolism, pharmacology)
• Cyclic Nucleotide Phosphodiesterases, Type 3
• Cyclic Nucleotide Phosphodiesterases, Type 5
• Humans
• Hypertension, Pulmonary (enzymology)
• Male
• Myocytes, Smooth Muscle (cytology, drug effects, enzymology)
• Pulmonary Artery (cytology, drug effects, enzymology)
• Rats
• Rats, Wistar
• Tosyllysine Chloromethyl Ketone (pharmacology)