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Effect of phosphodiesterase 10 inhibitor on pulmonary smooth muscle cell proliferation and signaling pathways

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MerkelCaroline-2021-07-20.pdf (1.247Mb)
Date
2020
Author
Merkel, Caroline
Advisors/Reviewers
Schermuly, Ralph
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http://dx.doi.org/10.22029/jlupub-303
Abstract

Pulmonary arterial hypertension (PAH) is a progressive lung disease due to contraction of arteries and remodeling leading to increased resistance and increased blood pressure in lung circulation. Genesis of the disease is promoted by up or down regulation of many mediators. Two of those mediators are believed to be the second messengers cyclic ... adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). The amounts of these second messengers were found to be decreased in experimental studies and in PAH patients. The degradation of cAMP and cGMP is regulated by phosphodiesterases (PDE). PDE reduce second messenger levels and thus favor PAH. Inhibition of PDE 1, 3, 4 and 5 showed amelioration of PAH in studies. PDE5 inhibitors belong to the established therapies. Although specific therapeutic drugs have been developed in last decades, still there is no cure for PAH available. To date, knowledge about the possible influence of newly discovered families of PDE (PDE 7-11) on PAH is poor. Up to now, PDE10 has mostly been investigated in neuronal diseases with promising results. In the field of PAH, PDE 10 is almost unknown. Interestingly, PDE 10 was reported to be increased in pulmonary arteries of monocrotaline induced hypertension in rat. The aim of this study was to investigate if PDE 10 is a possible treatment target for PAH. For this investigation, the effect of PDE 10 on human smooth muscle cells was characterized. Smooth muscle cells of patients with idiopathic pulmonary hypertension were reported to be hyperproliferative when compared to cells of healthy individuals. The new, selective PDE10-inhibitor, PF 3188212, stopped hyperproliferation in these cells. On the molecular level, inhibition of PDE10 leads to the activation of the cAMP/protein kinase A/cAMP-response element-binding protein axis. Another factor that is influenced by PDE 10 is cyclin D1. This cell cycle protein is required for progression through the G1-Phase of the cell cycle and therefore promotes cell proliferation. The PDE10-inhibitor PF-3188212 reduced levels of cyclin D1 significantly. The effects of PDE10 inhibition were not only seen on molecular level but also in an animal model. In the monocrotaline-rat model, treatment with PDE10 inhibitor PF-3188212 showed an improved right ventricular systolic pressure, an increased cardiac index, a reduced right heart hypertrophy, and, as an indicator for reduced right heart insufficiency, an improved tricuspid annular plane systolic excursion. Histological, reduced muscularization and medial wall thickness were documented. Taken together, all findings indicate a crucial role for PDE 10 in promoting and sustaining PAH. PF-3188212 is shown to be a potent PDE10 inhibitor.

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