RT Journal Article
SR Electronic
T1 Anti-contractile and anti-proliferative responses in human pulmonary arterial smooth muscle cells induced by ACT-333679, the active metabolite of selexipag, a non-prostanoid selective prostacyclin receptor agonist
JF European Respiratory Journal
JO Eur Respir J
FD European Respiratory Society
SP P2353
VO 44
IS Suppl 58
A1 John Gatfield
A1 Katalin Menyhart
A1 Oliver Nayler
YR 2014
UL http://erj.ersjournals.com/content/44/Suppl_58/P2353.abstract
AB Pulmonary arterial hypertension (PAH) is characterized by pulmonary vasoconstriction and vascular remodeling. Pulmonary arterial smooth muscle cells (PASMC) are major contributors to PAH pathology by displaying increased contractile and proliferative behavior. Stimulation of the prostacyclin (IP) receptor in PASMC leads to intracellular cyclic AMP accumulation, and increases in cAMP levels are known to reduce cellular proliferation and to inhibit cellular contraction via cellular hyperpolarization and cytoskeletal desensitization.In this study we analyzed the signaling cascades and phenotypic changes in human PASMC induced by the non-prostanoid IP receptor agonist ACT-333679, the active metabolite of the oral experimental PAH drug selexipag. ACT-333679 potently induced intracellular cAMP accumulation (EC50=265 nM) and mediated long-lasting (>10h) membrane potential hyperpolarization (EC50=32 nM). Impedance measurements showed that ACT-333679 induced long-lasting (>10h) and pronounced PASMC shape change (EC50= 4.3 nM). Additionally, ACT-333679 inhibited platelet-derived growth factor-BB-stimulated proliferation (3H-thymidine incorporation) in PASMC (IC50=2.9 nM).In summary, ACT-333679 activated a GPCR signaling cascade in PASMC leading to cAMP accumulation, cellular hyperpolarization and shape change, as well as inhibition of cellular proliferation. ACT-333679 potency increased ∼100-fold from the receptor-proximal cAMP readout to the receptor-distal therapeutically-relevant phenotypic readouts.