RT Journal Article
SR Electronic
T1 Comparison of current therapies against endothelin-induced growth in pulmonary smooth arterial muscle cells (PASMCs) derived from patients with pulmonary arterial hypertension
JF European Respiratory Journal
JO Eur Respir J
FD European Respiratory Society
SP P2355
VO 44
IS Suppl 58
A1 Jigisha Patel
A1 David Abraham
A1 Andrew Nelson
A1 Adam Silverstein
A1 Lucie Clapp
YR 2014
UL http://erj.ersjournals.com/content/44/Suppl_58/P2355.abstract
AB Pulmonary arterial hypertension (PAH) is a highly proliferative, vascular remodelling disease leading to heart failure and death. Endothelin-1 (ET-1) levels are raised and correlate with a poor outcome in PAH. Agents targeting the prostacyclin, ET-1 and cyclic GMP pathway are widely used to treat PAH but no direct comparison of multiple agents from all three pathways exists in vitro. Aim: To compare effects of prostacyclin mimetics (iloprost, treprostinil and MRE-269), tadalafil (PDE5 inhibitor), riociguat (guanylyl cyclase activator) and ET-1 receptor antagonists (ETRAs), bosentan and macitentan on cell proliferation in PASMCs derived from PAH patients (n=5). Methods: PASMCs were incubated in serum ± ET-1 (0.001-300nM). Drugs were evaluated in cells treated with 3nM ET-1 and serum. Cell proliferation was assessed using an MTS assay. Results: ET-1 modestly increased proliferation (1.5 fold at 100nM), but when combined with serum, the magnitude and potency of ET-1 was enhanced 3 and 10 fold, respectively. All drugs reduced proliferation with a rank order of the lowest (0.1nM-1000nM) dose to significantly (P<0.05) inhibit being treprostinil>riociguat≥MRE-269≥tadalafil=iloprost>>macitentan≥bosentan. ETRAs decreased (≥3 fold) while cGMP elevating agents increased (≥10 fold) the potency of treprostinil when combined. Conclusion: The efficacy of the different PAH therapies to inhibit ET-1 induced growth in PASMCs derived from PAH patients varied 10,000 fold. Prostacyclins and cGMP elevating agents, especially when combined, appear more effective antiproliferative agents than ETRAs.