Abstract 12091: Aldosterone Enhances Cardiac Rupture After Myocardial Infarction Through Calcium/Calmodulin-Dependent Protein Kinase II
Excessive activation of β-adrenergic, angiotensin II, and aldosterone signaling pathways promotes mortality after myocardial infarction (MI), while antagonist drugs targeting these pathways are core therapies for treating post-MI patients. The multifunctional calcium/calmodulin-dependent protein kinase II (CaMKII) is activated by catecholamines and angiotensin II, and CaMKII inhibition prevents isoproterenol- and angiotensin II-mediated cardiomyopathy. Here we ask the hypothesis if aldosterone and CaMKII participated in common responses to MI by developing a mouse MI model supplemented by aldosterone infusion (MI+Aldo) to approximate plasma aldosterone levels measured in MI patients. We find that aldosterone exerts direct toxic actions on myocardium by oxidative activation of CaMKII, causing cardiac rupture and increased mortality in mice after MI (65.5% for aldosterone versus 31.0% for vehicle, P=0.007, n≥19 mice per treatment). Aldosterone oxidizes CaMKII by recruiting NADPH oxidase, and hyperactive CaMKII promotes matrix metalloproteinase 9 (MMP9) expression in cardiomyocytes. We find enhanced MMP9 expression in cardiomyocytes isolated from the MI region in MI+Aldo wildtype mice, suggesting that myocardial MMP9 may be essential for enhancing rupture in the MI+Aldo model. We also identified increased MMP9 from myocardium in the MI region of patients who died of MI-related cardiac rupture, but not in patients who died of MI without rupture, suggesting that our findings in mice were relevant to patients. Myocardial CaMKII inhibition, over-expression of methionine sulfoxide reductase A, an enzyme that reduces oxidized CaMKII, or NADPH oxidase knockout gave protection from aldosterone-enhanced post-MI cardiac rupture. These findings support the conclusion that oxidized myocardial CaMKII mediates cardiotoxic effects of aldosterone on cardiac matrix, establishing CaMKII as a nodal signal for the neurohumoral pathways associated with poor outcomes after MI. Our study provides a mechanic rationale for clinical testing of whether currently available aldosterone antagonist drugs administered immediately after the diagnosis of MI can reduce acute mortality, by minimizing the likelihood of myocardial rupture.
- © 2011 by American Heart Association, Inc.