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Insulin-Induced Laminin Expression Promotes a Hypercontractile Airway Smooth Muscle Phenotype

¹ Department of Molecular Pharmacology, University Centre for Pharmacy, University of Groningen, The Netherlands; and ² Department of Physiology, National University of Singapore, Singapore

Correspondence and requests for reprints should be addressed to Bart G. J. Dekkers, M.Sc., Department of Molecular Pharmacology, University centre for Pharmacy, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands. E-mail: B.G.J.Dekkers{at}rug.nl

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 2, β1, and 1 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 β1-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.

Key Words: ASM phenotype • laminin • insulin • Rho kinase • PI3-kinase

CLINICAL RELEVANCE The current study reveals new mechanisms involved in the maturation of airway smooth muscle cells to a contractile phenotype as observed in asthma. It also provides more insight into the effects of insulin on airway smooth muscle.

 

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