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.

Porcine colonization of the Americas: a 60k SNP story

“…PDE10A and PDE11A are expressed in components of the trigeminovascular pain signaling system (Kruse et al, 2009). PDE10A is also involved in progressive pulmonary vascular remodeling, increasing its expression in some pulmonary diseases (Tian et al, 2011). Finally, interleukin 21 signaling has a critical role in promoting the lung inflammatory response to acute pneumovirus infection (Spolski et al, 2012).…”

EETs and CYP2J2 inhibit TNF-α-induced apoptosis in pulmonary artery endothelial cells and TGF-β1-induced migration in pulmonary artery smooth muscle cells

“…PAECs and PASMCs were cultured from porcine pulmonary arteries as previously described (18,21). PAECs and PASMCs, which were used between passages 2 and 6, were isolated from porcine pulmonary arteries obtained from a local abattoir within 1 h of slaughter.…”

“…The cells were cultured in an incubator at 37˚C and maintained in a humidified atmosphere with 5% CO 2 . The purity and identity of the endothelial cells and smooth muscle cells were verified by their typical morphological patterns and by immunofluorescent staining for factor VIII-related antigen and α-smooth muscle actin (α-SMA), respectively (16,21). All passages were performed using 0.05% trypsin and 0.02% EDTA.…”

Chemoproteomics Demonstrates Target Engagement and Exquisite Selectivity of the Clinical Phosphodiesterase 10A Inhibitor MP-10 in Its Native Environment

“…[8][9][10] Besides its impact on brain pathways, PDE10A has also been shown to be involved in the regulation of proliferative states in pulmonary hypertension and colon cancer. 11,12 Therefore, PDE10A inhibitors are promising pharmaceuticals and demonstration of their efficacy to ameliorate disease symptoms is actively being pursued by several drug companies. 2 Pfizer's PDE10A inhibitor MP-10 (PF-2545920) was found to be ineffective in a 4-week monotherapy trial investigating the effect of the drug on the acute exacerbation of psychosis in patients suffering from schizophrenia 13 Chemical proteomic technologies allow the characterization of the spectrum of protein-drug interactions and the measurement of target engagement of a particular drug in its native environment.…”