Heat Shock–Related Protein 20 Peptide Decreases Human Airway Constriction Downstream of β2-Adrenergic Receptor

Autor: Dawn C. Newcomb, Kasia Goleniewska, Alex Banathy, Padmini Komalavilas, R. Stokes Peebles, Kelly L. Boyd, Joyce Cheung-Flynn
Rok vydání: 2016
Předmět:
0301 basic medicine
Muscle Relaxation
Sus scrofa
Clinical Biochemistry
Peptide
Mice
0302 clinical medicine
Adrenergic beta-2 Receptor Antagonists
Cell Movement
Stress Fibers
Receptor
Lung
Original Research
chemistry.chemical_classification
biology
respiratory system
Constriction
Cell biology
Muscle relaxation
Bronchial Hyperreactivity
medicine.symptom
Muscle Contraction
Pulmonary and Respiratory Medicine
Ovalbumin
Myocytes
Smooth Muscle
Inflammation
Filamentous actin
03 medical and health sciences
otorhinolaryngologic diseases
medicine
Animals
Humans
HSP20 Heat-Shock Proteins
Molecular Biology
Actin
business.industry
Muscle
Smooth
Cell Biology
Allergens
Actin cytoskeleton
Actins
respiratory tract diseases
030104 developmental biology
030228 respiratory system
chemistry
Immunology
biology.protein
Carbachol
Receptors
Adrenergic
beta-2
Peptides
business
Zdroj: American Journal of Respiratory Cell and Molecular Biology. 55:225-233
ISSN: 1535-4989
1044-1549
DOI: 10.1165/rcmb.2015-0139oc
Popis: 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.
Databáze: OpenAIRE
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