Pulmonary arterial hypertension (PAH) is a progressive disease defined by anelevation of pulmonary vascular resistance due to sustained vessel contractionand enhanced vascular remodeling. The abnormal tone and remodeling in thepulmonary vasculature are believed to be related, at least in part, to thedecrease of cyclic nucleotide levels that are controlled by cyclic nucleotidephosphodiesterases (PDEs).PDEs, of which 11 families have been identified, maintain homeostasis of thesecond messengers by catalyzing the hydrolysis of cAMP and cGMP withdiverse compartmentalization and substrate specificities. Interestingly,increased expression of some PDE isoforms has been observed in PAH andbeneficial effects of PDE5 inhibitors, PDE1 inhibitors and PDE3/4 inhibitorshave been reported in clinical or experimental PAH. The role of PDE7-11 inPAH has not been investigated, thus we aimed to investigate the expressionprofile of those higher isoforms. In addition, we were interested in thecontribution of these enzymes to the pathophysiology of PAH using the wellestablishedmonocrotaline (MCT)-induced pulmonary hypertensive rat model.In this study, a prominent increase of PDE10A expression was observedamong the multiple newly identified PDEs (PDE7-11) which are all present inlung tissue. Interestingly, the upregulation of PDE10A is specific in thepulmonary vasculature of pulmonary hypertensive subjects without significantchanges in the systemic vasculature such as aorta or femoral artery.As one of the most recently described PDEs, PDE10A is characterized as acAMP-PDE and a cAMP-inhibited cGMP-PDE. Research on PDE10 is mainlyfocused on neurological studies because of its abundant expression in the brain.We demonstrated for the first time the predominant localization of PDE10A inthe media of the small pulmonary arteries and nuclear compartmentalization inpulmonary arterial smooth muscle cells (PASMCs). In accordance, bothPDE10A expression and cAMP hydrolyzing activity are remarkably increased inPASMCs from MCT-induced PH rats as compared to control rats, suggesting acontribution of PDE10A to the proliferative phenotype of PASMCs in theprocess of PH. Futher more, PDE10A immunoreactivity is strongly increased inpulmonary arteries of IPAH patient lung sections as compared to the donors,indicating clinical relevance of the findings obtained from the MCT model.The anti-proliferative effect of PDE10 inhibition is proved to be largely relevantto an increase of intracellular cAMP levels that may subsequently alterdownstream signaling events such as phosphorylation of the cAMP responseelement binding protein (CREB). In our investigation, we found that inhibition ofPDE10A by employing a selective inhibitor of PDE10 (papaverine) or PDE10Aspecific small interfering RNA (siRNA) promoted intracellular cAMP generation,induced CREB phosphorylation and attenuated proliferation of PASMCs fromMCT-induced PH rats.Furthermore, treating MCT-PH rats with the PDE10 inhibitor papaverine for 14days by intravenous infusion markedly reduced right ventricular systolicpressure values as well as total pulmonary vascular resistance index, withouteffects on the systemic arterial pressure. In addition, the percentage of fullymuscularized peripheral pulmonary arteries was significantly decreased.Taken together, this study supports a central role of PDE10A in progressivepulmonary vascular remodeling and suggests a novel therapeutic opportunityfor the treatment of pulmonary arterial hypertension.
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