title: 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.
  
  
  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: University of Giessen Lung Centre, Justus-Liebig-Universität Giessen, Klinikstrasse 36, 35392 Giessen, Germany. ralph.schermuly@uglc.de
authors: Ralph Theo
authors: RT
authors: Schermuly
authors: Soni Savai
authors: SS
authors: Pullamsetti
authors: Grazyna
authors: G
authors: Kwapiszewska
authors: Rio
authors: R
authors: Dumitrascu
authors: Xia
authors: X
authors: Tian
authors: Norbert
authors: N
authors: Weissmann
authors: Hossein Ardeschir
authors: HA
authors: Ghofrani
authors: Christina
authors: C
authors: Kaulen
authors: Torsten
authors: T
authors: Dunkern
authors: Christian
authors: C
authors: Schudt
authors: Robert
authors: R
authors: Voswinckel
authors: Jiang
authors: J
authors: Zhou
authors: Arun
authors: A
authors: Samidurai
authors: Walter
authors: W
authors: Klepetko
authors: Renate
authors: R
authors: Paddenberg
authors: Wolfgang
authors: W
authors: Kummer
authors: Werner
authors: W
authors: Seeger
authors: Friedrich
authors: F
authors: Grimminger
mesh_terms: D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000378:metabolism; D000818:Animals; D002455:Cell Division; D002908:Chronic Disease; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D004247:DNA / Q000096:biosynthesis; D004195:Disease Models, Animal; D006801:Humans; D006976:Hypertension, Pulmonary / Q000378:metabolism* / Q000628:therapy*; D017380:Hypertrophy, Right Ventricular / Q000378:metabolism / Q000628:therapy; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000201:enzymology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D011651:Pulmonary Artery / Q000166:cytology / Q000201:enzymology*; D051381:Rats; D015854:Up-Regulation / Q000502:physiology
chemical_list: D010726:Phosphodiesterase Inhibitors; D004247:DNA; D010727:Phosphoric Diester Hydrolases; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1; C517265:PDE1A protein, human; C517272:PDE1C protein, human; C517273:Pde1C protein, mouse; C517274:Pde1C protein, rat; C517263:Pde1a protein, rat; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517381:PDE5A protein, human; C517382:Pde5a protein, mouse; C517384:Pde5a protein, rat; D015056:1-Methyl-3-isobutylxanthine