title: Oxidation of CaMKII determines the cardiotoxic effects of aldosterone.
abstract: Excessive activation of the β-adrenergic, angiotensin II (Ang II) and aldosterone signaling pathways promotes mortality after myocardial infarction, and antagonists targeting these pathways are core therapies for treating this condition. Catecholamines and Ang II activate the multifunctional Ca(2+)/calmodulin-dependent protein kinase II (CaMKII), the inhibition of which prevents isoproterenol-mediated and Ang II-mediated cardiomyopathy. Here we show that aldosterone exerts direct toxic actions on myocardium by oxidative activation of CaMKII, causing cardiac rupture and increased mortality in mice after myocardial infarction. Aldosterone induces CaMKII oxidation by recruiting NADPH oxidase, and this oxidized and activated CaMKII promotes matrix metalloproteinase 9 (MMP9) expression in cardiomyocytes. Myocardial CaMKII inhibition, overexpression of methionine sulfoxide reductase A (an enzyme that reduces oxidized CaMKII) or NADPH oxidase deficiency prevented aldosterone-enhanced cardiac rupture after myocardial infarction. These findings show that oxidized myocardial CaMKII mediates the cardiotoxic effects of aldosterone on the cardiac matrix and establish CaMKII as a nodal signal for the neurohumoral pathways associated with poor outcomes after myocardial infarction.
authors.affiliation: Department of Molecular Physiology and Biophysics, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA.
authors.forename: B Julie
authors.initials: BJ
authors.lastname: He
authors.forename: Mei-Ling A
authors.initials: ML
authors.lastname: Joiner
authors.forename: Madhu V
authors.initials: MV
authors.lastname: Singh
authors.forename: Elizabeth D
authors.initials: ED
authors.lastname: Luczak
authors.forename: Paari Dominic
authors.initials: PD
authors.lastname: Swaminathan
authors.forename: Olha M
authors.initials: OM
authors.lastname: Koval
authors.forename: William
authors.initials: W
authors.lastname: Kutschke
authors.forename: Chantal
authors.initials: C
authors.lastname: Allamargot
authors.forename: Jinying
authors.initials: J
authors.lastname: Yang
authors.forename: Xiaoqun
authors.initials: X
authors.lastname: Guan
authors.forename: Kathy
authors.initials: K
authors.lastname: Zimmerman
authors.forename: Isabella M
authors.initials: IM
authors.lastname: Grumbach
authors.forename: Robert M
authors.initials: RM
authors.lastname: Weiss
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Spitz
authors.forename: Curt D
authors.initials: CD
authors.lastname: Sigmund
authors.forename: W Matthijs
authors.initials: WM
authors.lastname: Blankesteijn
authors.forename: Stephane
authors.initials: S
authors.lastname: Heymans
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Mohler
authors.forename: Mark E
authors.initials: ME
authors.lastname: Anderson
mesh_terms: D000450:Aldosterone / Q000009:adverse effects*; D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000235:genetics / Q000378:metabolism*; D054715:Cardiotoxins / Q000009:adverse effects*; D002478:Cells, Cultured; D006321:Heart / Q000187:drug effects; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D051150:Methionine Sulfoxide Reductases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000473:pathology*; D019255:NADPH Oxidases / Q000378:metabolism; D010084:Oxidation-Reduction; D015398:Signal Transduction; D015854:Up-Regulation
chemical_list: D054715:Cardiotoxins; D000450:Aldosterone; D008156:Luciferases; D019255:NADPH Oxidases; D051150:Methionine Sulfoxide Reductases; C027219:methionine sulfoxide reductase; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse
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