title: Mechanical stimuli and IL-13 interact at integrin adhesion complexes to regulate expression of smooth muscle myosin heavy chain in airway smooth muscle tissue.
abstract: Airway smooth muscle phenotype may be modulated in response to external stimuli under physiological and pathophysiological conditions. The effect of mechanical forces on airway smooth muscle phenotype were evaluated in vitro by suspending weights of 0.5 or 1 g from the ends of canine tracheal smooth muscle tissues, incubating the weighted tissues for 6 h, and then measuring the expression of the phenotypic marker protein, smooth muscle myosin heavy chain (SmMHC). Incubation of the tissues at a high load significantly increased expression of SmMHC compared with incubation at low load. Incubation of the tissues at a high load also decreased activation of PKB/Akt, as indicated by its phosphorylation at Ser 473. Inhibition of Akt or phosphatidylinositol-3,4,5 triphosphate-kinase increased SmMHC expression in tissues at low load but did not affect SmMHC expression at high load. IL-13 induced a significant increase in Akt activation and suppressed the expression of SmMHC protein at both low and high loads. The role of integrin signaling in mechanotransduction was evaluated by expressing a PINCH (LIM1-2) fragment in the muscle tissues that prevents the membrane localization of the integrin-binding IPP complex (ILK/PINCH/α-parvin), and also by expressing an inactive integrin-linked kinase mutant (ILK S343A) that inhibits endogenous ILK activity. Both mutants inhibited Akt activation and increased expression of SmMHC protein at low load but had no effect at high load. These results suggest that mechanical stress and IL-13 both act through an integrin-mediated signaling pathway to oppositely regulate the expression of phenotypic marker proteins in intact airway smooth muscle tissues. The stimulatory effects of mechanical stress on contractile protein expression oppose the suppression of contractile protein expression mediated by IL-13; thus the imposition of mechanical strain may inhibit changes in airway smooth muscle phenotype induced by inflammatory mediators.
authors.affiliation: Dept. of Cellular & Integrative Physiology, Indiana Univ. School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Leena P
authors.initials: LP
authors.lastname: Desai
authors.forename: Yidi
authors.initials: Y
authors.lastname: Wu
authors.forename: Robert S
authors.initials: RS
authors.lastname: Tepper
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Gunst
mesh_terms: D000818:Animals; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004285:Dogs; D018793:Interleukin-13 / Q000494:pharmacology*; D040542:Mechanotransduction, Cellular; D008840:Microfilament Proteins / Q000378:metabolism*; D046912:Multiprotein Complexes / Q000378:metabolism*; D009119:Muscle Contraction / Q000187:drug effects; D018995:Myosin Heavy Chains / Q000096:biosynthesis* / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D024745:Smooth Muscle Myosins / Q000096:biosynthesis* / Q000378:metabolism; D013314:Stress, Mechanical; D014132:Trachea / Q000502:physiology*; D000099200:Scaffold Protein ILK
chemical_list: D004268:DNA-Binding Proteins; D018793:Interleukin-13; D008840:Microfilament Proteins; D046912:Multiprotein Complexes; D018995:Myosin Heavy Chains; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D024745:Smooth Muscle Myosins; D000099200:Scaffold Protein ILK