title: Heat Shock-Related Protein 20 Peptide Decreases Human Airway Constriction Downstream of β2-Adrenergic Receptor.
abstract: Severe bronchospasm refractory to β-agonists is a challenging aspect of asthma therapy, and novel therapeutics are needed. β-agonist-induced airway smooth muscle (ASM) relaxation is associated with increases in the phosphorylation of the small heat shock-related protein (HSP) 20. We hypothesized that a transducible phosphopeptide mimetic of HSP20 (P20 peptide) causes relaxation of human ASM (HASM) by interacting with target(s) downstream of the β2-adrenergic receptor (β2AR) pathway. The effect of the P20 peptide on ASM contractility was determined in human and porcine ASM using a muscle bath. The effect of the P20 peptide on filamentous actin dynamics and migration was examined in intact porcine ASM and cultured primary HASM cells. The efficacy of the P20 peptide in vivo on airway hyperresponsiveness (AHR) was determined in an ovalbumin (OVA) sensitization and challenge murine model of allergic airway inflammation. P20 peptide caused dose-dependent relaxation of carbachol-precontracted ASM and blocked carbachol-induced contraction. The β2AR inhibitor, (±)-1-[2,3-(dihydro-7-methyl-1H-inden-4-yl)oxy]-3-[(1-methylethyl)amino]-2-butanol hydrochloride (ICI 118,551), abrogated isoproterenol but not P20 peptide-mediated relaxation. The P20 peptide decreased filamentous actin levels in intact ASM, disrupted stress fibers, and inhibited platelet-derived growth factor-induced migration of HASM cells. The P20 peptide treatment reduced methacholine-induced AHR in OVA mice without affecting the inflammatory response. These results suggest that the P20 peptide decreased airway constriction and disrupted stress fibers through regulation of the actin cytoskeleton downstream of β2AR. Thus, the P20 peptide may be a potential therapeutic for asthma refractory to β-agonists.
authors.affiliation: Departments of 1 Surgery.
authors.forename: Alex
authors.initials: A
authors.lastname: Banathy
authors.affiliation: Departments of 1 Surgery.
authors.forename: Joyce
authors.initials: J
authors.lastname: Cheung-Flynn
authors.affiliation: 2 Medicine, and.
authors.forename: Kasia
authors.initials: K
authors.lastname: Goleniewska
authors.affiliation: 3 Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee; and.
authors.forename: Kelly L
authors.initials: KL
authors.lastname: Boyd
authors.affiliation: 2 Medicine, and.
authors.forename: Dawn C
authors.initials: DC
authors.lastname: Newcomb
authors.affiliation: 2 Medicine, and.|4 Veterans Affairs Tennessee Valley Healthcare System, Nashville, Tennessee.
authors.forename: R Stokes
authors.initials: RS
authors.lastname: Peebles
authors.affiliation: Departments of 1 Surgery.|4 Veterans Affairs Tennessee Valley Healthcare System, Nashville, Tennessee.
authors.forename: Padmini
authors.initials: P
authors.lastname: Komalavilas
mesh_terms: D000199:Actins / Q000378:metabolism; D058672:Adrenergic beta-2 Receptor Antagonists / Q000494:pharmacology; D000485:Allergens / Q000009:adverse effects; D000818:Animals; D016535:Bronchial Hyperreactivity / Q000473:pathology; D002217:Carbachol; D002465:Cell Movement / Q000187:drug effects; D003250:Constriction; D050886:HSP20 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000473:pathology; D008168:Lung / Q000187:drug effects / Q000503:physiopathology*; D051379:Mice; D009119:Muscle Contraction / Q000187:drug effects*; D009126:Muscle Relaxation / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000503:physiopathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D010047:Ovalbumin / Q000009:adverse effects; D010455:Peptides / Q000494:pharmacology*; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism*; D022502:Stress Fibers / Q000187:drug effects / Q000378:metabolism; D034421:Sus scrofa
chemical_list: D000199:Actins; D058672:Adrenergic beta-2 Receptor Antagonists; D000485:Allergens; D050886:HSP20 Heat-Shock Proteins; D010455:Peptides; D018343:Receptors, Adrenergic, beta-2; D002217:Carbachol; D010047:Ovalbumin
keywords: airway smooth muscle relaxation; asthma; filamentous actin; ovalbumin mouse model; peptide therapeutic