Published Online
on April 16, 2007

A more recent version of this article appeared on May 1, 2007

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Submitted on November 16, 2006
Accepted on February 20, 2007

Phosphodiesterase 1 Upregulation in Pulmonary Arterial Hypertension. Target for Reverse-Remodeling Therapy

Ralph Theo Schermuly PhD^*, Soni Savai Pullamsetti PhD, Grazyna Kwapiszewska PhD, Rio Dumitrascu MD, PhD, Xia Tian MSc, Norbert Weissmann PhD, Hossein Ardeschir Ghofrani MD, Christina Kaulen MD, Torsten Dunkern PhD, Christian Schudt PhD, Robert Voswinckel MD, Jiang Zhou MSc, Arun Samidurai PhD, Walter Klepetko MD, Renate Paddenberg PhD, Wolfgang Kummer MD, Werner Seeger MD, and Friedrich Grimminger MD, PhD

From the University of Giessen Lung Centre (R.T.S., S.S.P., R.D., X.T., N.W., H.A.G., C.K., R.V., J.Z., A.S., W.S., F.G.), Giessen, Germany; Department of Pathology (G.K.) and Department of Anatomy and Cell Biology (R.P., W.K.), Justus Liebig University Giessen, Giessen, Germany; Department of Biochemistry 2 Inflammation (T.D., C.S.), Altana Pharma, Konstanz, Germany; and Department of Cardiothoracic Surgery (W.K.), University of Vienna, Vienna, Austria.

^* To whom correspondence should be addressed. E-mail: ralph.schermuly{at}uglc.de.

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.

Key words: cardiovascular diseases • hypertension, pulmonary • muscle, smooth • phosphodiesterases • pharmacology

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