title: Phosphodiesterase 10A upregulation contributes to pulmonary vascular remodeling.
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.
authors.affiliation: Medical Clinic II/V, University Hospital, Giessen, Germany.
authors.forename: Xia
authors.initials: X
authors.lastname: Tian
authors.forename: Christina
authors.initials: C
authors.lastname: Vroom
authors.forename: Hossein Ardeschir
authors.initials: HA
authors.lastname: Ghofrani
authors.forename: Norbert
authors.initials: N
authors.lastname: Weissmann
authors.forename: Ewa
authors.initials: E
authors.lastname: Bieniek
authors.forename: Friedrich
authors.initials: F
authors.lastname: Grimminger
authors.forename: Werner
authors.initials: W
authors.lastname: Seeger
authors.forename: Ralph Theo
authors.initials: RT
authors.lastname: Schermuly
authors.forename: Soni Savai
authors.initials: SS
authors.lastname: Pullamsetti
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D000242:Cyclic AMP / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D054708:Cyclic Nucleotide Phosphodiesterases, Type 7 / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D008168:Lung / Q000098:blood supply* / Q000201:enzymology* / Q000503:physiopathology; D008297:Male; D016686:Monocrotaline; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D010208:Papaverine / Q000494:pharmacology / Q000627:therapeutic use; D010727:Phosphoric Diester Hydrolases / Q000235:genetics / Q000378:metabolism*; D011651:Pulmonary Artery / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014019:Tissue Donors; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C508137:Creb1 protein, rat; D017362:Cyclic AMP Response Element-Binding Protein; D034741:RNA, Small Interfering; D016686:Monocrotaline; D010208:Papaverine; D000242:Cyclic AMP; C119843:PDE10A protein, human; C512064:PDE10A protein, rat; D010727:Phosphoric Diester Hydrolases; D054708:Cyclic Nucleotide Phosphodiesterases, Type 7