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1 Molecular Pharmacology, University of Groningen, Groningen, Netherlands
2 Physiology & Internal Medicine, and Section of Respiratory Disease, University of Manitoba, Winnipeg, Canada; Biology of Breathing Theme, Manitoba Institute of Child Health, Winnipeg, Canada
3 Molecular Pharmacology, University of Groningen, Antonius Deusinglaan 1, Groningen, 9713 AV, Netherlands; Physiology & Internal Medicine, and Section of Respiratory Disease, University of Manitoba, Winnipeg, Canada; Biology of Breathing Theme, Manitoba Institute of Child Health, Winnipeg, Canada
4 Medical Genetics, University of British Columbia, Vancouver, Canada
5 Physiology & Internal Medicine, and Section of Respiratory Disease, University of Manitoba, Canada; Biology of Breathing Theme, Manitoba Institute of Child Health, Canada
6 Biology of Breathing Theme, Manitoba Institute of Child Health, Winnipeg, Canada
* To whom correspondence should be addressed. E-mail: d.schaafsma{at}rug.nl.
We have previously demonstrated that long-term exposure of bovine tracheal smooth muscle (BTSM) strips to insulin induces a functional hypercontractile phenotype. To elucidate molecular mechanisms by which insulin might induce maturation of contractile phenotype airway smooth muscle (ASM) cells, we investigated effects of insulin stimulation in serum-free primary BTSM cell cultures on protein accumulation of specific contractile phenotypic markers, and on the abundance and -stability of mRNA encoding these markers. In addition, we used microscopy to assess insulin effects on ASM cell morphology, phenotype, and induction of PI-3-kinase signaling. It was demonstrated that protein and mRNA levels of smooth muscle specific contractile phenotypic markers, including sm-myosin, are significantly increased after stimulation of cultured BTSM cells with insulin (1 µM) for 8 days as compared to cells treated with serum-free media, while mRNA stability was unaffected. In addition, insulin-treatment promoted the formation of large, elongate ASM cells, characterized by dramatic accumulation of contractile phenotype marker proteins and phosphorylated p70S6K (downstream target of PI-3-kinase associated with ASM maturation). Insulin effects on protein accumulation and cell morphology were abrogated by combined pretreatment with the Rho-kinase inhibitor Y-27632 (1 µM) or the PI-3-kinase inhibitor LY-294002 (10 µM), indicating that insulin increases the expression of contractile phenotypic markers in BTSM in a Rho-kinase and PI-3-kinase dependent fashion. In conclusion, insulin increases transcription and protein expression of contractile phenotypic markers in ASM. This could have important implications for the use of recently approved aerosolized insulin formulations in diabetes mellitus.
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