Published ahead of print on April 7, 2005, doi:10.1164/rccm.200411-1587OC
Am. J. Respir. Crit. Care Med., Volume 172, Number 1, July 2005, 105-113
A more recent version of this article appeared on July 1, 2005
Submitted on November 25, 2004
Accepted on March 18, 2005
Anti-proliferative Effects of Phosphodiesterase Type 5 Inhibition in Human Pulmonary Artery Cells
John Wharton1*, Julian W Strange1, Gigi MO Moller1, Ellena J Growcott1, Xiaohui Ren1, Angela P Franklyn1, Stephen C Phillips2, and Martin R Wilkins1
1 Section on Experimental Medicine and Toxicology, Hammersmith Hospital, Imperial College London, London, United Kingdom,
2 Pfizer Global Research and Development, Sandwich, Kent, United Kingdom
* To whom correspondence should be addressed. 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: 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, 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. The majority (~80%) of cyclic guanosine monophosphate hydrolysis in cultured cells was attributed to PDE5. Sildenafil induced a greater elevation of intracellular cyclic guanosine monophosphate levels compared to nitric oxide donors and BAY41-2272 (~10-fold versus ~2-fold) and co-treatment 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 analogues.
Conclusions: Phosphodiesterase type 5 is the main factor regulating cyclic guanosine monophosphate hydrolysis and downstream signaling in human PASMCs. The anti-proliferative effects of this signaling pathway may be significant in the chronic treatment of pulmonary hypertension with PDE5 inhibitors such as sildenafil.
Key words: Hypertension, pulmonary; Cyclic nucleotides; Cell proliferation
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