title: Insulin-induced laminin expression promotes a hypercontractile airway smooth muscle phenotype.
abstract: Airway smooth muscle (ASM) plays a key role in the development of airway hyperresponsiveness and remodeling in asthma, which may involve maturation of ASM cells to a hypercontractile phenotype. In vitro studies have indicated that long-term exposure of bovine tracheal smooth muscle (BTSM) to insulin induces a functional hypercontractile, hypoproliferative phenotype. Similarly, the extracellular matrix protein laminin has been found to be involved in both the induction and maintenance of a contractile ASM phenotype. Using BTSM, we now investigated the role of laminins in the insulin-induced hypercontractile, hypoproliferative ASM phenotype. The results demonstrate that insulin-induced hypercontractility after 8 days of tissue culture was fully prevented by combined treatment of BTSM-strips with the laminin competing peptides Tyr-Ile-Gly-Ser-Arg (YIGSR) and Arg-Gly-Asp-Ser (RGDS). YIGSR also prevented insulin-induced increases in sm-myosin expression and abrogated the suppressive effects of prolonged insulin treatment on platelet-derived growth factor-induced DNA synthesis in cultured cells. In addition, insulin time-dependently increased laminin alpha2, beta1, and gamma1 chain protein, but not mRNA abundance in BTSM strips. Moreover, as previously found for contractile protein accumulation, signaling through PI3-kinase- and Rho kinase-dependent pathways was required for the insulin-induced increase in laminin abundance and contractility. Collectively, our results indicate a critical role for beta1-containing laminins, likely laminin-211, in the induction of a hypercontractile, hypoproliferative ASM phenotype by prolonged insulin exposure. Increased laminin production by ASM could be involved in the increased ASM contractility and contractile protein expression in asthma. Moreover, the results may be of interest for the use of inhaled insulin administrations by diabetics.
authors.affiliation: Department of Molecular Pharmacology, University centre for Pharmacy, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands. B.G.J.Dekkers@rug.nl
authors.forename: Bart G J
authors.initials: BG
authors.lastname: Dekkers
authors.forename: Dedmer
authors.initials: D
authors.lastname: Schaafsma
authors.forename: Thai
authors.initials: T
authors.lastname: Tran
authors.forename: Johan
authors.initials: J
authors.lastname: Zaagsma
authors.forename: Herman
authors.initials: H
authors.lastname: Meurs
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D002417:Cattle; D002867:Chromones / Q000494:pharmacology; D004261:DNA Replication / Q000187:drug effects; D066298:In Vitro Techniques; D007328:Insulin / Q000494:pharmacology* / Q000633:toxicity; D007537:Isometric Contraction / Q000187:drug effects; D007797:Laminin / Q000096:biosynthesis*; D016210:Methacholine Chloride / Q000494:pharmacology; D051379:Mice; D009025:Morpholines / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects*; D009130:Muscle, Smooth / Q000187:drug effects* / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology; D010641:Phenotype; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D012333:RNA, Messenger / Q000032:analysis; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014132:Trachea / Q000187:drug effects* / Q000378:metabolism; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000502:physiology
chemical_list: D002867:Chromones; D007328:Insulin; D007797:Laminin; D016210:Methacholine Chloride; D009025:Morpholines; D009842:Oligopeptides; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D012333:RNA, Messenger; D054460:rho-Associated Kinases; C102645:laminin alpha 2; C089141:laminin gamma 1; C081571:tyrosyl-isoleucyl-glycyl-seryl-arginine; C084098:laminin A; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C046617:arginyl-glycyl-aspartyl-serine