Oxidation of CaMKII determines the cardiotoxic effects of aldosterone. Nat Med 2011 Nov 13;17(12):1610-8
Date
11/15/2011Pubmed ID
22081025Pubmed Central ID
PMC3332099DOI
10.1038/nm.2506Scopus ID
2-s2.0-84856100794 (requires institutional sign-in at Scopus site) 201 CitationsAbstract
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.
Author List
He BJ, Joiner ML, Singh MV, Luczak ED, Swaminathan PD, Koval OM, Kutschke W, Allamargot C, Yang J, Guan X, Zimmerman K, Grumbach IM, Weiss RM, Spitz DR, Sigmund CD, Blankesteijn WM, Heymans S, Mohler PJ, Anderson MEAuthor
Curt Sigmund PhD Chair, Professor in the Physiology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AldosteroneAnimals
Calcium-Calmodulin-Dependent Protein Kinase Type 2
Cardiotoxins
Cells, Cultured
Heart
Humans
Luciferases
Male
Matrix Metalloproteinase 9
Methionine Sulfoxide Reductases
Mice
Mice, Knockout
Myocardial Infarction
NADPH Oxidases
Oxidation-Reduction
Signal Transduction
Up-Regulation
