@article{0e4649b23a22498c9e5d241635caa52d,
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.",
author = "He, {B. Julie} and Joiner, {Mei Ling A.} and Singh, {Madhu V.} and Luczak, {Elizabeth D.} and Swaminathan, {Paari Dominic} and Koval, {Olha M.} and William Kutschke and Chantal Allamargot and Jinying Yang and Xiaoqun Guan and Kathy Zimmerman and Grumbach, {Isabella M.} and Weiss, {Robert M.} and Spitz, {Douglas R.} and Sigmund, {Curt D.} and Blankesteijn, {W. Matthijs} and Stephane Heymans and Mohler, {Peter J.} and Anderson, {Mark E.}",
note = "Funding Information: We are grateful for discussions with K. Campbell, W. Nauseef and F. Abboud (University of Iowa). We acknowledge the technical contributions of D. Farley and M. Scheel (University of Iowa). We thank N. Sinclair, P. Yarolem and J. Schwarting (University of Iowa) for their technical expertise in generating transgenic mice. J. Robbins (University of Cincinnati) provided the αMHC complementary DNA (cDNA) for creating the transgenic mice. E. Olson (University of Texas Southwestern) provided mice harboring the MEF2-lacZ reporter gene. MsrA−/− mice were provided by the late E. Stadtman of the US National Institutes of Health. Transgenic mice were engineered at the University of Iowa Transgenic Animal Facility, and viral constructs were generated at the University of Iowa Gene Vector Transfer Core, which are both funded by the US National Institutes of Health. We acknowledge support by the US National Institutes of Health (1F30HL-095325 to B.J.H., RR-017369 to R.M.W., P30 CA086862 and R01CA133114 to D.R.S., R01HL083422 to P.J.M., and R01HL70250, R01HL079031 and R01HL096652 to M.E.A.) and by a grant (08CVD01) from the Fondation Leducq as part of the {\textquoteleft}Alliance for CaMKII Signaling in Heart{\textquoteright}. S.H. received a Vidi grant from the Netherlands Organization for Scientific Research (91796338) and research grants from the Netherlands Heart Foundation (NHS 2007B036 and 2008B011), Research Foundation–Flanders (FWO 1183211N, 1167610N, G074009N), European Union, FP7-HEALTH-2010, MEDIA, Large scale integrating project.",
year = "2011",
month = dec,
doi = "10.1038/nm.2506",
language = "English (US)",
volume = "17",
pages = "1610--1618",
journal = "Nature medicine",
issn = "1078-8956",
publisher = "Nature Publishing Group",
number = "12",
}