Oxidation of CaMKII determines the cardiotoxic effects of aldosterone

• DOI: 10.1038/nm.2506
• Publication Date: 2011-11-13T19:23:38Z
• Authors: B Julie He; Mei-ling A Joiner; Madhu V Singh; Elizabeth D Luczak; Paari Dominic Swa...; Olha M Koval; William Kutschke; Chantal Allamargot; Jinying Yang; Xiaoqun Guan; Kathy Zimmerman; Isabella M Grumbach; Robert M Weiss; Douglas R Spitz; Curt D Sigmund; W Matthijs Blanke...; Stephane Heymans; Peter J Mohler; Mark E Anderson
• Keywords: Male; Mice, Knockout; 0301 basic medicine; 0303 health sciences; Myocardial Infarction; NADPH Oxidases; Heart; Cardiotoxins; Up-Regulation; 3. Good health; Mice; 03 medical and health sciences; Matrix Metalloproteinase 9; Methionine Sulfoxide Reductases; Animals; Humans; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Luciferases; Aldosterone; Oxidation-Reduction; Cells, Cultured; Signal Transduction

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.