Overactivation of the sympathetic nervous system and the renin-angiotensin-aldosterone system after a myocardial infarction promotes heart failure and sudden death. The pathological consequences of increased β-adrenergic and angiotensin II (Ang II) signaling depend on activation of myocardial Ca2+/calmodulin-dependent protein kinase II (CaMKII). He et al. used a mouse model system to explore the mechanisms whereby aldosterone signaling contributes to heart failure. Aldosterone infusion increased cardiac reactive oxygen species (ROS) within 15 minutes, an effect blunted in mice lacking functional NADPH oxidase. Noting that Ang II activates myocardial CaMKII through the oxidation of two methionines in the CaMKII regulatory domain, the authors determined that aldosterone increased the amount of oxidized cardiac CaMKII (ox-CaMKII) and Ca2+/calmodulin-autonomous CaMKII activity. Aldosterone also increased ROS abundance and ox-CaMKII in cultured neonatal myocytes, effects inhibited by a mineralocorticoid antagonist, an NADPH oxidase inhibitor, or a dominant-negative form of Rac1 (a small GTPase required in endothelial cells for mineralocorticoid receptor–mediated activation of NADPH oxidase). Compared with wild-type mice, transgenic mice with increased cardiac methionine sulfoxide reductase (MsrA) showed decreased aldosterone-stimulated CamKII oxidation, without decreased cardiac ROS production. Mice subjected to myocardial infarction had increased ox-CAMKII, autonomous CaMKII activity, and mortality when infused with concentrations of aldosterone comparable to those seen in high-risk individuals with high concentrations of circulating aldosterone postinfarction, with excess mortality resulting from cardiac rupture. Analyses of the effects on cardiac rupture postinfarction in various transgenic mouse models revealed that inhibition of myocardial CaMKII (AC3-I mice) protected mice from the adverse effects of aldosterone, as did loss of NADPH oxidase activity or increased cardiac MsrA, whereas MsrA–/– mice had increased mortality. Matrix metalloproteinase 9 (MMP9) contributes to mouse cardiac rupture, and gene array analysis and quantitative RT-PCR indicated that AC3-I mice had decreased postinfarction Mmp9 expression compared with wild-type mice. Immunofluorescence analysis of cardiomyocytes isolated from regions of infarct showed changes in MMP9 abundance consistent with the changes in expression, and analyses of human heart tissue indicated that increased MMP9 was associated with cardiac rupture. Aldosterone enhanced MMP9 activity in cultured neonatal myocytes, an effect that depended on CaMKII activity. Sequence analysis revealed a putative binding site for myocyte enhancer factor 2 (MEF2), which is activated downstream of CaMKII, in the Mmp9 promoter. Analyses of MEF2-lacz transgenic mice indicated that aldosterone activated cardiac MEF2, and analyses of Mmp9-promoter–driven reporters expressed in myocytes indicated that the identified MEF2-binding site was crucial for aldosterone’s stimulation of Mmp9 transcription. Thus, the authors conclude that the cardiotoxic effects of aldosterone depend on the oxidative activation of CaMKII and that CaMKII is a “master” node for neurohumoral pathways associated with excess mortality after myocardial infarction.
B. J. He, M.-l. A. Joiner, M. V . Singh, E. D. Luczak, P. D. Swaminathan, O. M. Koval, W. Kutschke, C. Allamargot , J. Yang, X. Guan, K. Zimmerman, I. M. Grumbach, R. M. Weiss, D. R. Spitz, C. D. Sigmund, W. M. Blankesteijn, S. Heymans, P. J. Mohler, M. E. Anderson, Oxidation of CaMKII determines the cardiotoxic effects of aldosterone. Nat. Med. 17, 1610–1618 (2011). [PubMed]