CaMKII is essential for the proasthmatic effects of oxidation

Sci Transl Med. 2013 Jul 24;5(195):195ra97. doi: 10.1126/scitranslmed.3006135.

Abstract

Increased reactive oxygen species (ROS) contribute to asthma, but little is known about the molecular mechanisms connecting increased ROS with characteristic features of asthma. We show that enhanced oxidative activation of the Ca(2+)/calmodulin-dependent protein kinase (ox-CaMKII) in bronchial epithelium positively correlates with asthma severity and that epithelial ox-CaMKII increases in response to inhaled allergens in patients. We used mouse models of allergic airway disease induced by ovalbumin (OVA) or Aspergillus fumigatus (Asp) and found that bronchial epithelial ox-CaMKII was required to increase a ROS- and picrotoxin-sensitive Cl(-) current (ICl) and MUC5AC expression, upstream events in asthma progression. Allergen challenge increased epithelial ROS by activating NADPH oxidases. Mice lacking functional NADPH oxidases due to knockout of p47 and mice with epithelial-targeted transgenic expression of a CaMKII inhibitory peptide or wild-type mice treated with inhaled KN-93, an experimental small-molecule CaMKII antagonist, were protected against increases in ICl, MUC5AC expression, and airway hyperreactivity to inhaled methacholine. Our findings support the view that CaMKII is a ROS-responsive, pluripotent proasthmatic signal and provide proof-of-concept evidence that CaMKII is a therapeutic target in asthma.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Intranasal
  • Animals
  • Asthma / drug therapy
  • Asthma / enzymology*
  • Asthma / metabolism
  • Benzylamines / administration & dosage
  • Benzylamines / therapeutic use
  • Blotting, Western
  • Bronchi / metabolism
  • Bronchi / pathology
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / antagonists & inhibitors
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / genetics
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / metabolism*
  • Female
  • Humans
  • In Vitro Techniques
  • Male
  • Mice
  • NADPH Oxidases / metabolism
  • Ovalbumin / pharmacology
  • Oxidation-Reduction
  • Protein Kinase Inhibitors / administration & dosage
  • Protein Kinase Inhibitors / therapeutic use
  • Reactive Oxygen Species / metabolism
  • Real-Time Polymerase Chain Reaction
  • Sulfonamides / administration & dosage
  • Sulfonamides / therapeutic use

Substances

  • Benzylamines
  • Protein Kinase Inhibitors
  • Reactive Oxygen Species
  • Sulfonamides
  • KN 93
  • Ovalbumin
  • NADPH Oxidases
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2