Phosphodiesterase 10A Upregulation Contributes to Pulmonary Vascular Remodeling

Xia Tian,Christina Vroom,Hossein Ardeschir Ghofrani,Werner Seeger,Ewa Bieniek,Norbert Weissmann,Ralph Theo Schermuly,Soni Savai Pullamsetti,Friedrich Grimminger,Wael El-Rifai

doi:10.1371/journal.pone.0018136

Abstract

Phosphodiesterases (PDEs) modulate the cellular proliferation involved in the pathophysiology of pulmonary hypertension (PH) by hydrolyzing cAMP and cGMP. The present study was designed to determine whether any of the recently identified PDEs (PDE7-PDE11) contribute to progressive pulmonary vascular remodeling in PH. All in vitro experiments were performed with lung tissue or pulmonary arterial smooth muscle cells (PASMCs) obtained from control rats or monocrotaline (MCT)-induced pulmonary hypertensive (MCT-PH) rats, and we examined the effects of the PDE10 inhibitor papaverine (Pap) and specific small interfering RNA (siRNA). In addition, papaverine was administrated to MCT-induced PH rats from day 21 to day 35 by continuous intravenous infusion to examine the in vivo effects of PDE10A inhibition. We found that PDE10A was predominantly present in the lung vasculature, and the mRNA, protein, and activity levels of PDE10A were all significantly increased in MCT PASMCs compared with control PASMCs. Papaverine and PDE10A siRNA induced an accumulation of intracellular cAMP, activated cAMP response element binding protein and attenuated PASMC proliferation. Intravenous infusion of papaverine in MCT-PH rats resulted in a 40%–50% attenuation of the effects on pulmonary hypertensive hemodynamic parameters and pulmonary vascular remodeling. The present study is the first to demonstrate a central role of PDE10A in progressive pulmonary vascular remodeling, and the results suggest a novel therapeutic approach for the treatment of PH.

Highlights

Pulmonary arterial hypertension (PAH) is a fatal disease characterized by progressively elevated pulmonary vascular resistance, which results from vasoconstriction, vascular remodeling and in situ thrombosis
In the isolated pulmonary arterial smooth muscle cells (PASMCs) at passage 2, we only observed the presence of PDE7A, PDE7B, PDE8A, PDE10A and PDE11A, and we found a 2.5-fold increase in PDE7A and PDE10A mRNA expression in MCT PASMCs compared with control PASMCs (Figure 1B)
The cGMP-binding regulatory (GAF) domain of PDE10A is unique compared to the GAF domains of other PDE families because it is the only one that binds to cAMP instead of cGMP, which may contribute to the preferential hydrolysis of Camp [26]

Summary

Introduction

Pulmonary arterial hypertension (PAH) is a fatal disease characterized by progressively elevated pulmonary vascular resistance, which results from vasoconstriction, vascular remodeling and in situ thrombosis. These events lead to right ventricular hypertrophy and right heart failure [1]. Because cAMP and cGMP are ubiquitous second messengers, PDEs are involved in many important signaling pathways that regulate proliferation, migration, and differentiation [6,7]. Sub-isoforms of PDE4 have been shown to have diverse functions in subcellular pools of cAMP that result from compartmentalization [9]

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