Journal article
Oxidation of CaMKII determines cardiotoxic effects of aldosterone
Nature medicine, Vol.17(12), pp.1610-1618
12/2011
DOI: 10.1038/nm.2506
PMCID: PMC3332099
PMID: 22081025
Abstract
Excessive activation of β-adrenergic, angiotensin II, and aldosterone (Aldo) signaling pathways promotes mortality after myocardial infarction (MI), while antagonist drugs targeting these pathways are core therapies for treating post-MI patients. Catecholamines and angiotensin II activate the multifunctional Ca
2+
/calmodulin-dependent protein kinase II (CaMKII), and CaMKII inhibition prevents isoproterenol- and angiotensin II-mediated cardiomyopathy. Here we show that Aldo exerts direct toxic actions on myocardium by oxidative activation of CaMKII, causing cardiac rupture and increased mortality in mice after MI. Aldo oxidizes CaMKII by recruiting NADPH oxidase, and oxidized CaMKII promotes matrix metalloproteinase 9 (Mmp9) expression in cardiomyocytes. Myocardial CaMKII inhibition, over-expression of methionine sulfoxide reductase A, an enzyme that reduces oxidized CaMKII, or NADPH oxidase inhibition prevented Aldo-enhanced post-MI cardiac rupture. These findings show oxidized myocardial CaMKII mediates cardiotoxic effects of Aldo on cardiac matrix and establish CaMKII as a nodal signal for the neurohumoral pathways associated with poor outcomes after MI.
Details
- Title: Subtitle
- Oxidation of CaMKII determines cardiotoxic effects of aldosterone
- Creators
- B. Julie He - Department of Molecular Physiology and Biophysics, The University of Iowa Carver College of Medicine, Iowa City, IA, USAMei-Ling A Joiner - Internal Medicine, The University of Iowa Carver College of Medicine, Iowa City, IA, USAMadhu V Singh - Internal Medicine, The University of Iowa Carver College of Medicine, Iowa City, IA, USAElizabeth D Luczak - Internal Medicine, The University of Iowa Carver College of Medicine, Iowa City, IA, USAPaari Dominic Swaminathan - Internal Medicine, The University of Iowa Carver College of Medicine, Iowa City, IA, USAOlha M Koval - Internal Medicine, The University of Iowa Carver College of Medicine, Iowa City, IA, USAWilliam Kutschke - Internal Medicine, The University of Iowa Carver College of Medicine, Iowa City, IA, USAChantal Allamargot - Central Microscopy Research Facilities, The University of Iowa Carver College of Medicine, Iowa City, IA, USAJinying Yang - Internal Medicine, The University of Iowa Carver College of Medicine, Iowa City, IA, USAXiaoqun Guan - Internal Medicine, The University of Iowa Carver College of Medicine, Iowa City, IA, USAKathy Zimmerman - Department of Veterans Affairs Medical Center, The University of Iowa Carver College of Medicine, Iowa City, IA, USAIsabella M Grumbach - Internal Medicine, The University of Iowa Carver College of Medicine, Iowa City, IA, USARobert M Weiss - Internal Medicine, The University of Iowa Carver College of Medicine, Iowa City, IA, USADouglas R Spitz - Free Radical and Radiation Biology Program, Department of Radiation Oncology, The University of Iowa Carver College of Medicine, Iowa City, IA, USACurt D Sigmund - Department of Molecular Physiology and Biophysics, The University of Iowa Carver College of Medicine, Iowa City, IA, USAW. Matthijs Blankesteijn - Department of Pharmacology and Toxicology, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The NetherlandsStephane Heymans - Center for Heart Failure Research, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The NetherlandsPeter J Mohler - Department of Molecular Physiology and Biophysics, The University of Iowa Carver College of Medicine, Iowa City, IA, USAMark E Anderson - Department of Molecular Physiology and Biophysics, The University of Iowa Carver College of Medicine, Iowa City, IA, USA
- Resource Type
- Journal article
- Publication Details
- Nature medicine, Vol.17(12), pp.1610-1618
- DOI
- 10.1038/nm.2506
- PMID
- 22081025
- PMCID
- PMC3332099
- NLM abbreviation
- Nat Med
- ISSN
- 1078-8956
- eISSN
- 1546-170X
- Grant note
- R01 HL070250-10 || HL / National Heart, Lung, and Blood Institute : NHLBI R01 HL096652-04 || HL / National Heart, Lung, and Blood Institute : NHLBI K26 RR017369-05 || RR / National Center for Research Resources : NCRR
- Language
- English
- Date published
- 12/2011
- Academic Unit
- Molecular Physiology and Biophysics; Core Research Facilities; Pathology; Cardiovascular Medicine; Biology; Radiation Oncology; Anesthesia; Neuroscience and Pharmacology; Endocrinology and Metabolism; Internal Medicine
- Record Identifier
- 9984047733802771
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