TY - JOUR T1 - Obligatory role of MEK/ERK/RSK90 in the mitogenic responses of human pulmonary artery smooth muscle cells JF - European Respiratory Journal JO - Eur Respir J VL - 44 IS - Suppl 58 SP - P309 AU - Isabel Blanco AU - Todd K. Kolb AU - Laura Johnston AU - Paul M. Hassoun AU - Rachel L. Damico Y1 - 2014/09/01 UR - http://erj.ersjournals.com/content/44/Suppl_58/P309.abstract N2 - PAH is a high mortality disease with no medical cure resulting in increased PAP culminating in RV failure and premature death.The vasculopathy of PAH is characterized by medial hypertrophy coupled with obliterative intimal and plexiform lesions.Current therapies do not reverse the vasculopathy.There is a need to identify additional therapeutic targets.The vasculopathy of PAH is typified by increased rates of proliferation thus raising interest in identification of novel anti-proliferative therapeutic targets. Objective: To elucidate the role of MEK/ERK/RSK90 on mitogen-induced proliferation in human PASMC. Methods: PASMC were exposed to select mitogens such as ET-1, serotonin (5-HT) and PDGF for 24h and assessed for proliferative responses using the MTT assay.To assess the role of the MEK/ERK/RSK90 signaling pathway, cultures were preincubated with select MAP Kinase inhibitors including MAPK/ERK (extracellular signal-regulated kinase) kinase (MEK) inhibitor (PD98059), p90 Ribosomal S6 Kinase(RSK90) inhibitor (SL-0101) and 3-phosphoinositide-dependent protein kinase (PDK1) inhibitor (GSK2334470) vs vehicle. Results: Proliferative responses to ET-1, 5-HT and PDGF were dependent on the activity of MEK/ERK/RSK90 and PDK1.We observed an increase in proliferation ∼25% and when they were pharmacologically inhibited with MAP kinase inhibitors, there was also a significant decrease in mitogen-induced proliferation ∼50%. Conclusion: These data provide evidence of an obligatory role for the MEK/ERK/RSK90 signaling pathway in the proliferative responses of hPASMC and suggest that this pathway may be critical for pathologic remodeling in PAH and could represent a novel therapeutic target. ER -