Phosphodiesterase 1 Upregulation in Pulmonary Arterial Hypertension

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. Key Words: cardiovascular diseases Ⅲ hypertension, pulmonary Ⅲ muscle, smooth Ⅲ phosphodiesterases Ⅲ pharmacology P ulmonary arterial hypertension (PAH) is a severe disease with still largely unresolved pathogenesis. It is characterized by increased pulmonary vascular resistance and thus right ventricular (RV) afterload, which in the further course of the disease leads to RV failure and death. Both vasoconstriction and structural remodeling of the pulmonary vessels contribute to the progressive course of PAH, irrespective of different underlying causes. 1,2 New treatment concepts in pulmonary hypertension include local and systemic administration of prostacyclin and its analogues, inhalation of nitric oxide (NO), and endothelin receptor antagonists. 3,4 Recently, phosphodiesterase (PDE) 5 inhibitors have been demonstrated to be potent, selective pulmonary vasodilators. [5][6][7][8][9] Clinical Perspective p 2339PDEs hydrolyze the cyclic nucleotide second messengers cAMP and cGMP, which are known to play an important role in regulating vascular tone and smooth muscle cell (SMC) proliferation. 10 Members of the PDE1 gene family are activated by calcium/calmodulin and are therefore termed "cal- Received November 16, 2006; accepted February 20, 2007. 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, Ger...

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“…The experiments have been approved by the local ethics committee (Regierungspräsidium Darmstadt). Mice were exposed to chronic hypoxia (10% O 2 ) for 24 h in a ventilated chamber, as described previously (36). The level of hypoxia was held constant by an auto regulatory control unit (model 4010, O 2 controller; …”

Phosphodiesterase inhibitors for the treatment of pulmonary hypertension

“…PDE1 is expressed at low levels in pulmonary tissues under normal conditions [33]. However, recent studies have shown significant upregulation of this enzyme in proliferating pulmonary vasculature, indicating a pathogenic role under disease conditions [33][34][35].…”

Inhibition of MRP4 prevents and reverses pulmonary hypertension in mice

“…In recent years, phosphodiesterase type 5 (PDE5) inhibitors (sildenafil and tadalafil) have been approved for the treatment of PAH (7)(8)(9)(10)(11)(12). The levels of cAMP have also been shown to be reduced in PASMCs from PH patients, in line with an increased expression of PDE types 1 and 3 (13,14), also promoting PASMC proliferation. Prostacyclin analogs (epoprostenol, iloprost, and treprostinil) that increase PASMC cAMP levels have also been approved for the treatment of PAH (10,11,15).…”