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: B Julie He, Mei-Ling A Joiner, Madhu V Singh, Elizabeth D Luczak, Paari Dominic Swaminathan, 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 Blankesteijn, Stephane Heymans, Peter J Mohler, Mark E Anderson
• Journal: Nature medicine (Nat Med) Vol. 17 Issue 12 Pg. 1610-8 (Nov 13 2011) ISSN: 1546-170X [Electronic] United States
• PMID: 22081025 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Cardiotoxins
• Aldosterone
• Luciferases
• NADPH Oxidases
• Methionine Sulfoxide Reductases
• methionine sulfoxide reductase
• Calcium-Calmodulin-Dependent Protein Kinase Type 2
• Matrix Metalloproteinase 9
• Mmp9 protein, mouse

Topics

• Aldosterone (adverse effects)
• Animals
• Calcium-Calmodulin-Dependent Protein Kinase Type 2 (genetics, metabolism)
• Cardiotoxins (adverse effects)
• Cells, Cultured
• Heart (drug effects)
• Humans
• Luciferases (metabolism)
• Male
• Matrix Metalloproteinase 9 (genetics, metabolism)
• Methionine Sulfoxide Reductases (genetics, metabolism)
• Mice
• Mice, Knockout
• Myocardial Infarction (pathology)
• NADPH Oxidases (metabolism)
• Oxidation-Reduction
• Signal Transduction
• Up-Regulation