Phosphodiesterase 1 upregulation in pulmonary arterial hypertension: target for reverse-remodeling therapy.

Abstract

BACKGROUND:

Pulmonary arterial hypertension (PAH) is a life-threatening disease, characterized by vascular smooth muscle cell hyperproliferation. The calcium/calmodulin-dependent phosphodiesterase 1 (PDE1) may play a major role in vascular smooth muscle cell proliferation.

METHODS AND RESULTS:

We investigated the expression of PDE1 in explanted lungs from idiopathic PAH patients and animal models of PAH and undertook therapeutic intervention studies in the animal models. Strong upregulation of PDE1C in pulmonary arterial vessels in the idiopathic PAH lungs compared with healthy donor lungs was noted on the mRNA level by laser-assisted vessel microdissection and on the protein level by immunohistochemistry. In chronically hypoxic mouse lungs and lungs from monocrotaline-injected rats, PDE1A upregulation was detected in the structurally remodeled arterial muscular layer. Long-term infusion of the PDE1 inhibitor 8-methoxymethyl 3-isobutyl-1-methylxanthine in hypoxic mice and monocrotaline-injected rats with fully established pulmonary hypertension reversed the pulmonary artery pressure elevation, structural remodeling of the lung vasculature (nonmuscularized versus partially muscularized versus fully muscularized small pulmonary arteries), and right heart hypertrophy.

CONCLUSIONS:

Strong upregulation of the PDE1 family in pulmonary artery smooth muscle cells is noted in human idiopathic PAH lungs and lungs from animal models of PAH. Inhibition of PDE1 reverses structural lung vascular remodeling and right heart hypertrophy in 2 animal models. The PDE1 family may thus offer a new target for therapeutic intervention in pulmonary hypertension.

• Authors: Ralph Theo Schermuly, Soni Savai Pullamsetti, Grazyna Kwapiszewska, Rio Dumitrascu, Xia Tian, Norbert Weissmann, Hossein Ardeschir Ghofrani, Christina Kaulen, Torsten Dunkern, Christian Schudt, Robert Voswinckel, Jiang Zhou, Arun Samidurai, Walter Klepetko, Renate Paddenberg, Wolfgang Kummer, Werner Seeger, Friedrich Grimminger
• Journal: Circulation (Circulation) Vol. 115 Issue 17 Pg. 2331-9 (May 01 2007) ISSN: 1524-4539 [Electronic] United States
• PMID: 17438150 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Phosphodiesterase Inhibitors
• DNA
• Phosphoric Diester Hydrolases
• Cyclic Nucleotide Phosphodiesterases, Type 1
• PDE1A protein, human
• PDE1C protein, human
• Pde1C protein, mouse
• Pde1C protein, rat
• Pde1a protein, rat
• 3',5'-Cyclic-GMP Phosphodiesterases
• Cyclic Nucleotide Phosphodiesterases, Type 5
• PDE5A protein, human
• Pde5a protein, mouse
• Pde5a protein, rat
• 1-Methyl-3-isobutylxanthine

Topics

• 1-Methyl-3-isobutylxanthine (pharmacology)
• 3',5'-Cyclic-GMP Phosphodiesterases (metabolism)
• Animals
• Cell Division
• Chronic Disease
• Cyclic Nucleotide Phosphodiesterases, Type 1
• Cyclic Nucleotide Phosphodiesterases, Type 5
• DNA (biosynthesis)
• Disease Models, Animal
• Humans
• Hypertension, Pulmonary (metabolism, therapy)
• Hypertrophy, Right Ventricular (metabolism, therapy)
• Mice
• Muscle, Smooth, Vascular (cytology, enzymology)
• Phosphodiesterase Inhibitors (pharmacology)
• Phosphoric Diester Hydrolases (metabolism)
• Pulmonary Artery (cytology, enzymology)
• Rats
• Up-Regulation (physiology)