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Oxidation of CaMKII determines the cardiotoxic effects of aldosterone

Nature Medicine volume 17, pages 1610–1618 (2011)Cite this article

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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 Ca2+/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.

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Figure 1: Aldosterone induces ROS and CaMKII oxidation and activation.
Figure 2: Transgenic (TG) myocardial MsrA overexpression reduces CaMKII oxidation.
Figure 3: Aldosterone increases mortality after myocardial infarction (MI) by promoting myocardial rupture.
Figure 4: MMP9 expression in myocytes is associated with aldosterone and cardiac rupture.
Figure 5: Characterization of the inflammatory and fibrotic responses in AC3-I and WT mice after MI+Aldo treatment.
Figure 6: CaMKII promotes cardiac MMP9 expression and activity.

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Acknowledgements

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 'Alliance for CaMKII Signaling in Heart'. 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.

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Author notes

  1. Mei-ling A Joiner, Madhu V Singh, Elizabeth D Luczak and Paari Dominic Swaminathan: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Molecular Physiology and Biophysics, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA

    B Julie He & Mark E Anderson

  2. Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA

    B Julie He, Mei-ling A Joiner, Madhu V Singh, Elizabeth D Luczak, Paari Dominic Swaminathan, Olha M Koval, William Kutschke, Jinying Yang, Xiaoqun Guan, Isabella M Grumbach, Robert M Weiss & Mark E Anderson

  3. Central Microscopy Research Facilities, The University of Iowa, Iowa City, Iowa, USA

    Chantal Allamargot

  4. Department of Veterans Affairs Medical Center, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA

    Kathy Zimmerman & Robert M Weiss

  5. Department of Radiation Oncology, Free Radical and Radiation Biology Program, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA

    Douglas R Spitz

  6. Department of Pharmacology, University of Iowa Caver College of Medicine, Iowa City, Iowa, USA

    Curt D Sigmund

  7. Department of Pharmacology and Toxicology, Maastricht University, Maastricht, The Netherlands

    W Matthijs Blankesteijn

  8. Center for Heart Failure Research, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands

    Stephane Heymans

  9. ICIN–Netherlands Heart Institute, Utrecht, The Netherlands

    Stephane Heymans

  10. Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium

    Stephane Heymans

  11. Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Medical Center, Columbus, Ohio, USA

    Peter J Mohler

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Contributions

B.J.H. designed experiments, analyzed data and wrote the manuscript. M.A.J. designed experiments and assisted with the tissue and image analyses. M.V.S. assisted with the MPO activity assay, analyzed gene array data and assisted with qRT-PCR design and analysis. E.D.L. assisted with animal studies, immunoblotting, experimental design and data analysis. P.D.S. assisted with immunoblotting, experimental design and data analysis. O.M.K. assisted in cell culture isolation. W.K. performed mouse surgeries and analyzed data. C.A. performed immunostaining studies. J.Y. performed mouse studies and assisted with mouse models. X.G. assisted with subcloning work. K.Z. performed echocardiographic experiments and analyzed data. I.M.G. assisted in developing adenoviral constructs and edited the manuscript. R.M.W. designed echocardiographic studies, analyzed data and edited the manuscript. D.R.S. assisted with the MsrA transgenic mouse design and development of the MsrA assay, analyzed data and edited the manuscript. C.D.S. developed the MsrA transgenic mice, analyzed data and edited the manuscript. W.M.B., S.H. and P.J.M. designed experiments, analyzed data and edited the manuscript. M.E.A. designed experiments, analyzed data, co-wrote the manuscript and supervised the project.

Corresponding author

Correspondence to Mark E Anderson.

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Competing interests

M.E.A. has intellectual property claiming to treat myocardial infarction by CaMKII inhibition and is a co-founder of Allosteros Therapeutics, a biotech company aiming to develop enzyme-based therapies.

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He, B., Joiner, Ml., Singh, M. et al. Oxidation of CaMKII determines the cardiotoxic effects of aldosterone. Nat Med 17, 1610–1618 (2011). https://doi.org/10.1038/nm.2506

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