Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Oxidation of CaMKII determines the cardiotoxic effects of aldosterone

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

Subjects

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.

Access through your institution
Buy or subscribe

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

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.

Similar content being viewed by others

References

  1. Lopez, A.D., Mathers, C.D., Ezzati, M., Jamison, D.T. & Murray, C.J. Global and regional burden of disease and risk factors, 2001: systematic analysis of population health data. Lancet 367, 1747–1757 (2006).

    Article  Google Scholar 

  2. Zhang, R. et al. Calmodulin kinase II inhibition protects against structural heart disease. Nat. Med. 11, 409–417 (2005).

    Article  CAS  Google Scholar 

  3. Erickson, J.R. et al. A dynamic pathway for calcium-independent activation of CaMKII by methionine oxidation. Cell 133, 462–474 (2008).

    Article  CAS  Google Scholar 

  4. Gutierrez-Marcos, F.M. et al. Atrial natriuretic peptide in patients with acute myocardial infarction without functional heart failure. Eur. Heart J. 12, 503–507 (1991).

    Article  CAS  Google Scholar 

  5. Beygui, F. et al. High plasma aldosterone levels on admission are associated with death in patients presenting with acute ST-elevation myocardial infarction. Circulation 114, 2604–2610 (2006).

    Article  CAS  Google Scholar 

  6. Pitt, B. et al. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N. Engl. J. Med. 348, 1309–1321 (2003).

    Article  CAS  Google Scholar 

  7. Pitt, B. et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N. Engl. J. Med. 341, 709–717 (1999).

    Article  CAS  Google Scholar 

  8. Reilly, R.F. & Ellison, D.H. Mammalian distal tubule: physiology, pathophysiology, and molecular anatomy. Physiol. Rev. 80, 277–313 (2000).

    Article  CAS  Google Scholar 

  9. Rude, M.K. et al. Aldosterone stimulates matrix metalloproteinases and reactive oxygen species in adult rat ventricular cardiomyocytes. Hypertension 46, 555–561 (2005).

    Article  CAS  Google Scholar 

  10. Johar, S., Cave, A.C., Narayanapanicker, A., Grieve, D.J. & Shah, A.M. Aldosterone mediates angiotensin II-induced interstitial cardiac fibrosis via a Nox2-containing NADPH oxidase. FASEB J. 20, 1546–1548 (2006).

    Article  CAS  Google Scholar 

  11. Nakamura, S. et al. Possible association of heart failure status with synthetic balance between aldosterone and dehydroepiandrosterone in human heart. Circulation 110, 1787–1793 (2004).

    Article  CAS  Google Scholar 

  12. Rousseau, M.F. et al. Beneficial neurohormonal profile of spironolactone in severe congestive heart failure: results from the RALES neurohormonal substudy. J. Am. Coll. Cardiol. 40, 1596–1601 (2002).

    Article  CAS  Google Scholar 

  13. Huang, C.K., Zhan, L., Hannigan, M.O., Ai, Y. & Leto, T.L. P47(phox)-deficient NADPH oxidase defect in neutrophils of diabetic mouse strains, C57BL/6J-m db/db and db/+. J. Leukoc. Biol. 67, 210–215 (2000).

    Article  CAS  Google Scholar 

  14. Swaminathan, P.D. et al. Oxidized CaMKII causes cardiac sinus node dysfunction in mice. J. Clin. Invest. 121, 3277–3288 (2011).

    Article  CAS  Google Scholar 

  15. Kusch, M., Farman, N. & Edelman, I.S. Binding of aldosterone to cytoplasmic and nuclear receptors of the urinary bladder epithelium of Bufo marinus. Am. J. Physiol. 235, C82–C89 (1978).

    Article  CAS  Google Scholar 

  16. Iwashima, F. et al. Aldosterone induces superoxide generation via Rac1 activation in endothelial cells. Endocrinology 149, 1009–1014 (2008).

    Article  CAS  Google Scholar 

  17. Zimmerman, M.C. et al. Requirement for Rac1-dependent NADPH oxidase in the cardiovascular and dipsogenic actions of angiotensin II in the brain. Circ. Res. 95, 532–539 (2004).

    Article  CAS  Google Scholar 

  18. Weber, K.T. Aldosterone in congestive heart failure. N. Engl. J. Med. 345, 1689–1697 (2001).

    Article  CAS  Google Scholar 

  19. Swedberg, K., Eneroth, P., Kjekshus, J. & Wilhelmsen, L. Hormones regulating cardiovascular function in patients with severe congestive heart failure and their relation to mortality. CONSENSUS Trial Study Group. Circulation 82, 1730–1736 (1990).

    Article  CAS  Google Scholar 

  20. Matsumura, S. et al. Targeted deletion or pharmacological inhibition of MMP-2 prevents cardiac rupture after myocardial infarction in mice. J. Clin. Invest. 115, 599–609 (2005).

    Article  CAS  Google Scholar 

  21. Heymans, S. et al. Inhibition of plasminogen activators or matrix metalloproteinases prevents cardiac rupture but impairs therapeutic angiogenesis and causes cardiac failure. Nat. Med. 5, 1135–1142 (1999).

    Article  CAS  Google Scholar 

  22. Singh, M.V. et al. Ca2+/calmodulin-dependent kinase II triggers cell membrane injury by inducing complement factor B gene expression in the mouse heart. J. Clin. Invest. 119, 986–996 (2009).

    Article  CAS  Google Scholar 

  23. van den Borne, S.W. et al. Increased matrix metalloproteinase-8 and -9 activity in patients with infarct rupture after myocardial infarction. Cardiovasc. Pathol. 18, 37–43 (2009).

    Article  CAS  Google Scholar 

  24. Bradley, P.P., Priebat, D.A., Christensen, R.D. & Rothstein, G. Measurement of cutaneous inflammation: estimation of neutrophil content with an enzyme marker. J. Invest. Dermatol. 78, 206–209 (1982).

    Article  CAS  Google Scholar 

  25. Nahrendorf, M. et al. Activatable magnetic resonance imaging agent reports myeloperoxidase activity in healing infarcts and noninvasively detects the antiinflammatory effects of atorvastatin on ischemia-reperfusion injury. Circulation 117, 1153–1160 (2008).

    Article  CAS  Google Scholar 

  26. Kim, Y. et al. The MEF2D transcription factor mediates stress-dependent cardiac remodeling in mice. J. Clin. Invest. 118, 124–132 (2008).

    Article  CAS  Google Scholar 

  27. Wu, C.Y., Hsieh, H.L., Sun, C.C. & Yang, C.M. IL-1β induces MMP-9 expression via a Ca(2)-dependent CaMKII/JNK/c-JUN cascade in rat brain astrocytes. Glia 57, 1775–1789 (2009).

    Article  Google Scholar 

  28. Munaut, C. et al. Murine matrix metalloproteinase 9 gene. 5′-upstream region contains cis-acting elements for expression in osteoclasts and migrating keratinocytes in transgenic mice. J. Biol. Chem. 274, 5588–5596 (1999).

    Article  CAS  Google Scholar 

  29. Backs, J., Song, K., Bezprozvannaya, S., Chang, S. & Olson, E.N. CaM kinase II selectively signals to histone deacetylase 4 during cardiomyocyte hypertrophy. J. Clin. Invest. 116, 1853–1864 (2006).

    Article  CAS  Google Scholar 

  30. Naya, F.J., Wu, C., Richardson, J.A., Overbeek, P. & Olson, E.N. Transcriptional activity of MEF2 during mouse embryogenesis monitored with a MEF2-dependent transgene. Development 126, 2045–2052 (1999).

    CAS  PubMed  Google Scholar 

  31. Kolodziejczyk, S.M. et al. MEF2 is upregulated during cardiac hypertrophy and is required for normal post-natal growth of the myocardium. Curr. Biol. 9, 1203–1206 (1999).

    Article  CAS  Google Scholar 

  32. Chang, S. et al. Histone deacetylase 7 maintains vascular integrity by repressing matrix metalloproteinase 10. Cell 126, 321–334 (2006).

    Article  CAS  Google Scholar 

  33. Hiratsuka, S. et al. MMP9 induction by vascular endothelial growth factor receptor-1 is involved in lung-specific metastasis. Cancer Cell 2, 289–300 (2002).

    Article  CAS  Google Scholar 

  34. Timmins, J.M. et al. Calcium/calmodulin-dependent protein kinase II links ER stress with Fas and mitochondrial apoptosis pathways. J. Clin. Invest. 119, 2925–2941 (2009).

    Article  CAS  Google Scholar 

  35. Zhao, B.Q. et al. Role of matrix metalloproteinases in delayed cortical responses after stroke. Nat. Med. 12, 441–445 (2006).

    Article  CAS  Google Scholar 

  36. Khoo, M.S. et al. Death, cardiac dysfunction, and arrhythmias are increased by calmodulin kinase II in calcineurin cardiomyopathy. Circulation 114, 1352–1359 (2006).

    Article  CAS  Google Scholar 

  37. Backs, J. et al. The delta isoform of CaM kinase II is required for pathological cardiac hypertrophy and remodeling after pressure overload. Proc. Natl. Acad. Sci. USA 106, 2342–2347 (2009).

    Article  CAS  Google Scholar 

  38. Doerries, C. et al. Critical role of the NAD(P)H oxidase subunit p47phox for left ventricular remodeling/dysfunction and survival after myocardial infarction. Circ. Res. 100, 894–903 (2007).

    Article  CAS  Google Scholar 

  39. Kinugawa, S. et al. Treatment with dimethylthiourea prevents left ventricular remodeling and failure after experimental myocardial infarction in mice: role of oxidative stress. Circ. Res. 87, 392–398 (2000).

    Article  CAS  Google Scholar 

  40. Yusuf, S., Dagenais, G., Pogue, J., Bosch, J. & Sleight, P. Vitamin E supplementation and cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N. Engl. J. Med. 342, 154–160 (2000).

    Article  CAS  Google Scholar 

  41. Rapola, J.M. et al. Randomised trial of alpha-tocopherol and beta-carotene supplements on incidence of major coronary events in men with previous myocardial infarction. Lancet 349, 1715–1720 (1997).

    Article  CAS  Google Scholar 

  42. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of antioxidant vitamin supplementation in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 360, 23–33 (2002).

  43. Jauslin, M.L., Meier, T., Smith, R.A. & Murphy, M.P. Mitochondria-targeted antioxidants protect Friedreich Ataxia fibroblasts from endogenous oxidative stress more effectively than untargeted antioxidants. FASEB J. 17, 1972–1974 (2003).

    Article  CAS  Google Scholar 

  44. Chen, C.H. et al. Activation of aldehyde dehydrogenase-2 reduces ischemic damage to the heart. Science 321, 1493–1495 (2008).

    Article  CAS  Google Scholar 

  45. Tomaselli, G.F. & Barth, A.S. Sudden cardio arrest: oxidative stress irritates the heart. Nat. Med. 16, 648–649 (2010).

    Article  CAS  Google Scholar 

  46. Maack, C. et al. Oxygen free radical release in human failing myocardium is associated with increased activity of rac1-GTPase and represents a target for statin treatment. Circulation 108, 1567–1574 (2003).

    Article  CAS  Google Scholar 

  47. Dargie, H.J. Effect of carvedilol on outcome after myocardial infarction in patients with left-ventricular dysfunction: the CAPRICORN randomised trial. Lancet 357, 1385–1390 (2001).

    Article  CAS  Google Scholar 

  48. Dickstein, K. & Kjekshus, J. & OPTIMAAL Steering Committee of the OPTIMAAL Study Group. Effects of losartan and captopril on mortality and morbidity in high-risk patients after acute myocardial infarction: the OPTIMAAL randomised trial. Optimal Trial in Myocardial Infarction with Angiotensin Antagonist Losartan. Lancet 360, 752–760 (2002).

    Article  CAS  Google Scholar 

  49. Christensen, M.D. et al. Oxidized calmodulin kinase II regulates conduction following myocardial infarction: a computational analysis. PLOS Comput. Biol. 5, e1000583 (2009).

    Article  Google Scholar 

  50. Wehrens, X.H. & Doevendans, P.A. Cardiac rupture complicating myocardial infarction. Int. J. Cardiol. 95, 285–292 (2004).

    Article  Google Scholar 

  51. Pouleur, A.C. et al. Pathogenesis of sudden unexpected death in a clinical trial of patients with myocardial infarction and left ventricular dysfunction, heart failure or both. Circulation 122, 597–602 (2010).

    Article  Google Scholar 

  52. Fonarow, G.C., Lukas, M.A., Robertson, M., Colucci, W.S. & Dargie, H.J. Effects of carvedilol early after myocardial infarction: analysis of the first 30 days in Carvedilol Post-Infarct Survival Control in Left Ventricular Dysfunction (CAPRICORN). Am. Heart J. 154, 637–644 (2007).

    Article  CAS  Google Scholar 

  53. Ambrosioni, E., Borghi, C. & Magnani, B. The effect of the angiotensin-converting-enzyme inhibitor zofenopril on mortality and morbidity after anterior myocardial infarction. The Survival of Myocardial Infarction Long-Term Evaluation (SMILE) Study Investigators. N. Engl. J. Med. 332, 80–85 (1995).

    Article  CAS  Google Scholar 

  54. Beygui, F. et al. Rationale for an early aldosterone blockade in acute myocardial infarction and design of the ALBATROSS trial. Am. Heart J. 160, 642–648 (2010).

    Article  CAS  Google Scholar 

  55. Weiss, R.M., Ohashi, M., Miller, J.D., Young, S.G. & Heistad, D.D. Calcific aortic valve stenosis in old hypercholesterolemic mice. Circulation 114, 2065–2069 (2006).

    Article  Google Scholar 

  56. Thiel, W.H. et al. Proarrhythmic defects in Timothy syndrome require calmodulin kinase II. Circulation 118, 2225–2234 (2008).

    Article  CAS  Google Scholar 

  57. Mohler, P.J. et al. Defining the cellular phenotype of “ankyrin-B syndrome” variants: human ANK2 variants associated with clinical phenotypes display a spectrum of activities in cardiomyocytes. Circulation 115, 432–441 (2007).

    Article  Google Scholar 

  58. Li, H. et al. Calmodulin kinase II is required for Ang II-mediated vascular smooth muscle hypertrophy. Am. J. Physiol. Heart Circ. Physiol. 298, H688–H698 (2010).

    Article  CAS  Google Scholar 

  59. Brot, N., Weissbach, L., Werth, J. & Weissbach, H. Enzymatic reduction of protein-bound methionine sulfoxide. Proc. Natl. Acad. Sci. USA 78, 2155–2158 (1981).

    Article  CAS  Google Scholar 

  60. Owusu-Ansah, E., Yavari, A. & Banerjee, U. A protocol for in vivo detection of reactive oxygen species. Protocol Exchange doi:10.1038/nprot.2008.23 (2008).

    Article  CAS  Google Scholar 

Download references

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.

Author information

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

Authors
  1. B Julie He
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Mei-ling A Joiner
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. Madhu V Singh
    View author publications

    You can also search for this author inPubMed Google Scholar

  4. Elizabeth D Luczak
    View author publications

    You can also search for this author inPubMed Google Scholar

  5. Paari Dominic Swaminathan
    View author publications

    You can also search for this author inPubMed Google Scholar

  6. Olha M Koval
    View author publications

    You can also search for this author inPubMed Google Scholar

  7. William Kutschke
    View author publications

    You can also search for this author inPubMed Google Scholar

  8. Chantal Allamargot
    View author publications

    You can also search for this author inPubMed Google Scholar

  9. Jinying Yang
    View author publications

    You can also search for this author inPubMed Google Scholar

  10. Xiaoqun Guan
    View author publications

    You can also search for this author inPubMed Google Scholar

  11. Kathy Zimmerman
    View author publications

    You can also search for this author inPubMed Google Scholar

  12. Isabella M Grumbach
    View author publications

    You can also search for this author inPubMed Google Scholar

  13. Robert M Weiss
    View author publications

    You can also search for this author inPubMed Google Scholar

  14. Douglas R Spitz
    View author publications

    You can also search for this author inPubMed Google Scholar

  15. Curt D Sigmund
    View author publications

    You can also search for this author inPubMed Google Scholar

  16. W Matthijs Blankesteijn
    View author publications

    You can also search for this author inPubMed Google Scholar

  17. Stephane Heymans
    View author publications

    You can also search for this author inPubMed Google Scholar

  18. Peter J Mohler
    View author publications

    You can also search for this author inPubMed Google Scholar

  19. Mark E Anderson
    View author publications

    You can also search for this author inPubMed Google Scholar

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.

Ethics declarations

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.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–8 and Supplementary Methods (PDF 3566 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm.2506

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing