Phosphodiesterase 1 upregulation in pulmonary arterial hypertension: target for reverse-remodeling therapy.
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.
Schermuly
Ralph Theo
RT
University of Giessen Lung Centre, Justus-Liebig-Universität Giessen, Klinikstrasse 36, 35392 Giessen, Germany. ralph.schermuly@uglc.de
Pullamsetti
Soni Savai
SS
Kwapiszewska
Grazyna
G
Dumitrascu
Rio
R
Tian
Xia
X
Weissmann
Norbert
N
Ghofrani
Hossein Ardeschir
HA
Kaulen
Christina
C
Dunkern
Torsten
T
Schudt
Christian
C
Voswinckel
Robert
R
Zhou
Jiang
J
Samidurai
Arun
A
Klepetko
Walter
W
Paddenberg
Renate
R
Kummer
Wolfgang
W
Seeger
Werner
W
Grimminger
Friedrich
F
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
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