title: Iptakalim inhibits PDGF-BB-induced human airway smooth muscle cells proliferation and migration.
abstract: 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 (KATP) channels have been identified in ASMCs. Mount evidence has suggested that KATP channel openers can reduce airway hyperresponsiveness and alleviate airway remodeling. Opening K(+) channels triggers K(+) efflux, which leading to membrane hyperpolarization, preventing Ca(2+)entry through closing voltage-operated Ca(2+) channels. Intracellular Ca(2+) is the most important regulator of muscle contraction, cell proliferation and migration. K(+) efflux decreases Ca(2+) influx, which consequently influences ASMCs proliferation and migration. As a KATP 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 Ca(2+)/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 KATP 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 KATP channels. Altogether, our results highlighted a novel profile of Ipt as a potent option against the airway remodeling in chronic airway diseases.
authors.affiliation: Department of Respiratory Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, PR China.
authors.forename: Wenrui
authors.initials: W
authors.lastname: Liu
authors.affiliation: Department of Respiratory Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, PR China.
authors.forename: Hui
authors.initials: H
authors.lastname: Kong
authors.affiliation: Department of Respiratory Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, PR China.
authors.forename: Xiaoning
authors.initials: X
authors.lastname: Zeng
authors.affiliation: Department of Respiratory Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, PR China.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Respiratory Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, PR China.
authors.forename: Zailiang
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Respiratory Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, PR China.
authors.forename: Xiaopei
authors.initials: X
authors.lastname: Yan
authors.affiliation: Department of Respiratory Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, PR China.
authors.forename: Yanli
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Respiratory Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, PR China. Electronic address: wpxie@njmu.edu.cn.
authors.forename: Weiping
authors.initials: W
authors.lastname: Xie
authors.affiliation: Department of Respiratory Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, PR China. Electronic address: hongwang@njmu.edu.cn.
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D000077214:Becaplermin; D050882:CREB-Binding Protein / Q000378:metabolism; D015220:Calcium Channels / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005905:Glyburide / Q000494:pharmacology; D006801:Humans; D054086:KATP Channels / Q000378:metabolism; D008168:Lung / Q000166:cytology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D010766:Phosphorylation; D026902:Potassium Channel Blockers / Q000494:pharmacology; D011437:Propylamines / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D020574:Proto-Oncogene Proteins c-sis / Q000378:metabolism*; D059807:S Phase Cell Cycle Checkpoints / Q000187:drug effects
chemical_list: D015220:Calcium Channels; D054086:KATP Channels; C502260:N-(1-methylethyl)-1,1,2-trimethylpropylamine; D026902:Potassium Channel Blockers; D011437:Propylamines; D020574:Proto-Oncogene Proteins c-sis; D000077214:Becaplermin; D050882:CREB-Binding Protein; C494363:CREBBP protein, human; D051057:Proto-Oncogene Proteins c-akt; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D048049:Extracellular Signal-Regulated MAP Kinases; D005905:Glyburide
keywords: ATP sensitive potassium channel; Airway remodeling; Human airway smooth muscle cells; Iptakalim; Migration; Proliferation