Journal article
CaMKII Is Essential for the Proasthmatic Effects of Oxidation
Science translational medicine, Vol.5(195), pp.195ra97-195ra97
07/24/2013
DOI: 10.1126/scitranslmed.3006135
PMCID: PMC4331168
PMID: 23884469
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 (I
Cl
) 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 I
Cl
, MUC5AC expression, and airway hyper-reactivity to inhaled methacholine. Our findings support the view that CaMKII is a ROS-responsive, pluripotent pro-asthmatic signal and provide proof-of-concept evidence that CaMKII is a therapeutic target in asthma.
Details
- Title: Subtitle
- CaMKII Is Essential for the Proasthmatic Effects of Oxidation
- Creators
- Philip N Sanders - Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USAOlha M Koval - Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USAOmar A Jaffer - Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USAAnand M Prasad - Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USAThomas R Businga - Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USAJason A Scott - Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USAPatrick J Hayden - MatTek Corporation, 200 Homer Avenue, Ashland, MA 01721, USAElizabeth D Luczak - Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USADavid D Dickey - Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USAChantal Allamargot - Central Microscopy Research Facilities, University of Iowa, Iowa City, IA 52242, USAAlicia K Olivier - Department of Pathology, Medical Laboratories, University of Iowa, Iowa City, IA 52242, USADavid K Meyerholz - Department of Pathology, Medical Laboratories, University of Iowa, Iowa City, IA 52242, USAAlfred J Robison - Department of Physiology, Michigan State University, East Lansing, MI 48824, USADanny G Winder - Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN 37232, USATimothy S Blackwell - Department of Internal Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USARyszard Dworski - Department of Internal Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USADavid Sammut - Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton and NIHR Respiratory Bioscience Research Unit, Southampton General Hospital, Southampton, Hants SO16 6YD, UKBrett A Wagner - Free Radical and Radiation Biology Program, Department of Radiation Oncology, University of Iowa, Iowa City, IA 52242, USAGarry R Buettner - Free Radical and Radiation Biology Program, Department of Radiation Oncology, University of Iowa, Iowa City, IA 52242, USARobert M Pope - Proteomics Facility, University of Iowa, Iowa City, IA 52242, USAFrancis J Miller - Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USAMegan E Dibbern - Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USAHans Michael Haitchi - Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton and NIHR Respiratory Bioscience Research Unit, Southampton General Hospital, Southampton, Hants SO16 6YD, UKPeter J Mohler - The Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USAPeter H Howarth - Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton and NIHR Respiratory Bioscience Research Unit, Southampton General Hospital, Southampton, Hants SO16 6YD, UKJoseph Zabner - Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USAJoel N Kline - Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USAIsabella M Grumbach - Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USAMark E Anderson - Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
- Resource Type
- Journal article
- Publication Details
- Science translational medicine, Vol.5(195), pp.195ra97-195ra97
- DOI
- 10.1126/scitranslmed.3006135
- PMID
- 23884469
- PMCID
- PMC4331168
- NLM abbreviation
- Sci Transl Med
- ISSN
- 1946-6234
- eISSN
- 1946-6242
- Language
- English
- Date published
- 07/24/2013
- Academic Unit
- Pulmonary, Critical Care, and Occupational Medicine; Occupational and Environmental Health; Core Research Facilities; Pathology; Cardiovascular Medicine; Radiation Oncology; Medicine Administration; Internal Medicine
- Record Identifier
- 9984047755802771
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