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(Circulation. 2007;115:2331-2339.)
© 2007 American Heart Association, Inc.

Vascular Medicine

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; 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.

Correspondence to Ralph Schermuly, University of Giessen Lung Centre, Justus-Liebig-Universität Giessen, Klinikstrasse 36, 35392 Giessen, Germany. E-mail ralph.schermuly{at}uglc.de

Received November 16, 2006; accepted February 20, 2007.

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.

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