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Antiproliferative Effects of Phosphodiesterase Type 5 Inhibition in Human Pulmonary Artery Cells

Section on Experimental Medicine and Toxicology, Imperial College London, Hammersmith Hospital, London; and Pfizer Global Research and Development, Kent, United Kingdom

Correspondence and requests for reprints should be addressed to John Wharton, Ph.D., Section on Experimental Medicine and Toxicology, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 ONN, UK. E-mail: j.wharton{at}imperial.ac.uk

Rationale: Phosphodiesterase Type 5 (PDE5) inhibition represents a novel strategy for the treatment of pulmonary hypertension. Objectives: Our aim was to establish the distribution of PDE5 in the pulmonary vasculature and effects of PDE5 inhibition on pulmonary artery smooth muscle cells (PASMCs). Methods and Measurements: PDE5 expression was examined by immunohistochemistry and Western blotting, in both normal and hypertensive lung tissues. DNA synthesis, proliferation, PDE activity, and apoptosis were measured in distal human PASMCs treated with soluble guanylyl cyclase activators (nitric oxide donors and BAY41–2272) and sildenafil. Main Results: Cells containing PDE5 and -smooth muscle actin occurred throughout the pulmonary vasculature, including obstructive intimal lesions. Three molecular forms of PDE5 were identified and protein expression was greater in hypertensive than control lung tissue. Most cyclic guanosine monophosphate hydrolysis (about 80%) in cultured cells was attributed to PDE5. Sildenafil induced a greater elevation of intracellular cyclic guanosine monophosphate levels compared with nitric oxide donors and BAY41–2272 (about 10-fold versus about 2-fold) and cotreatment had a synergistic effect, increasing cyclic nucleotide levels up to 50-fold. Dual stimulation of soluble guanylyl cyclase and inhibition of PDE5 activities also had significant downstream effects, increasing phosphorylation of vasodilator-stimulated phosphoprotein, reducing DNA synthesis and cell proliferation, and stimulating apoptosis, and these effects were mimicked by cyclic guanosine monophosphate analogs. Conclusions: Phosphodiesterase Type 5 is the main factor regulating cyclic guanosine monophosphate hydrolysis and downstream signaling in human PASMCs. The antiproliferative effects of this signaling pathway may be significant in the chronic treatment of pulmonary hypertension with PDE5 inhibitors such as sildenafil.

Key Words: cell proliferation • cyclic nucleotides • hypertension, pulmonary

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