Iptakalim inhibits PDGF-BB-induced human airway smooth muscle cells proliferation and migration

Chronic airway diseases are characterized by airway remodeling which is attributed partly to the proliferation and migration of airway smooth muscle cells (ASMCs). ATP-sensitive potassium (K-ATP) channels have been identified in ASMCs. Mount evidence has suggested that K-ATP channel openers can reduce airway hyperresponsiveness and alleviate airway remodeling. Opening K+ channels triggers K+ efflux, which leading to membrane hyperpolarization, preventing Ca2+ entry through closing voltage-operated Ca2+ channels. Intracellular Ca2+ is the most important regulator of muscle contraction, cell proliferation and migration. K+ efflux decreases Ca2+ influx, which consequently influences ASMCs proliferation and migration. As a K-ATP channel opener, iptakalim (Ipt) has been reported to restrain the proliferation of pulmonary arterial smooth muscle cells (PASMCs) involved in vascular remodeling, while little is known about its impact on ASMCs. The present study was designed to investigate the effects of Ipt on human ASMCs and the mechanisms underlying. Results obtained from cell counting kit-8 (CCK-8), flow cytometry and 5-ethynyl-2'-deoxyuridine (EdU) incorporation showed that Ipt significantly inhibited platelet-derived growth factor (PDGF)-BB-induced ASMCs proliferation. ASMCs migration induced by PDGF-BB was also suppressed by Ipt in transwell migration and scratch assay. Besides, the phosphorylation of Ca2+/calmodulin-dependent kinase II (CaMKII), extracellular regulated protein kinases 1/2 (ERK1/2), protein kinase B (Akt), and cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) were as well alleviated by Ipt administration. Furthermore, we found that the inhibition of Ipt on the PDGF-BB-induced proliferation and migration in human ASMCs was blocked by glibenclamide (Gli), a selective K-ATP channel antagonist. These findings provide a strong evidence to support that Ipt antagonize the proliferating and migrating effects of PDGF-BB on human ASMCs through opening K-ATP channels. Altogether, our results highlighted a novel profile of Ipt as a potent option against the airway remodeling in chronic airway diseases. (C) 2015 Elsevier Inc. All rights reserved.