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:

Myocardial infarction accelerates atherosclerosis

Nature volume 487, pages 325–329 (2012)Cite this article

Subjects

Abstract

During progression of atherosclerosis, myeloid cells destabilize lipid-rich plaques in the arterial wall and cause their rupture, thus triggering myocardial infarction and stroke. Survivors of acute coronary syndromes have a high risk of recurrent events for unknown reasons. Here we show that the systemic response to ischaemic injury aggravates chronic atherosclerosis. After myocardial infarction or stroke, Apoe−/− mice developed larger atherosclerotic lesions with a more advanced morphology. This disease acceleration persisted over many weeks and was associated with markedly increased monocyte recruitment. Seeking the source of surplus monocytes in plaques, we found that myocardial infarction liberated haematopoietic stem and progenitor cells from bone marrow niches via sympathetic nervous system signalling. The progenitors then seeded the spleen, yielding a sustained boost in monocyte production. These observations provide new mechanistic insight into atherogenesis and provide a novel therapeutic opportunity to mitigate disease progression.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1: Increased inflammation in atherosclerotic plaques after MI.
Figure 2: Elevated levels of progenitor cells in the spleen ofApoe−/− mice after MI.
Figure 3: β3-Adrenoceptor-mediated progenitor release after MI.
Figure 4: Serial intravital imaging of progenitor release from the bone marrow.
Figure 5: Splenic progenitor engraftment after MI.

Similar content being viewed by others

References

  1. Goldstein, J. A. et al. Multiple complex coronary plaques in patients with acute myocardial infarction. N. Engl. J. Med. 343, 915–922 (2000)

    Article  CAS  Google Scholar 

  2. Milonas, C. et al. Effect of angiotensin-converting enzyme inhibition on one-year mortality and frequency of repeat acute myocardial infarction in patients with acute myocardial infarction. Am. J. Cardiol. 105, 1229–1234 (2010)

    Article  CAS  Google Scholar 

  3. Libby, P., Ridker, P. M. & Hansson, G. K. Progress and challenges in translating the biology of atherosclerosis. Nature 473, 317–325 (2011)

    Article  ADS  CAS  Google Scholar 

  4. Weber, C. & Noels, H. Atherosclerosis: current pathogenesis and therapeutic options. Nature Med. 17, 1410–1422 (2011)

    Article  CAS  Google Scholar 

  5. Randolph, G. J. The fate of monocytes in atherosclerosis. J. Thromb. Haemost. 7 (suppl. 1). 28–30 (2009)

    Article  CAS  Google Scholar 

  6. Charo, I. F. & Ransohoff, R. M. The many roles of chemokines and chemokine receptors in inflammation. N. Engl. J. Med. 354, 610–621 (2006)

    Article  CAS  Google Scholar 

  7. Galkina, E. & Ley, K. Immune and inflammatory mechanisms of atherosclerosis. Annu. Rev. Immunol. 27, 165–197 (2009)

    Article  CAS  Google Scholar 

  8. Ernst, E., Hammerschmidt, D. E., Bagge, U., Matrai, A. & Dormandy, J. A. Leukocytes and the risk of ischemic diseases. J. Am. Med. Assoc. 257, 2318–2324 (1987)

    Article  CAS  Google Scholar 

  9. Sabatine, M. S. et al. Relationship between baseline white blood cell count and degree of coronary artery disease and mortality in patients with acute coronary syndromes: a TACTICS-TIMI 18 substudy. J. Am. Coll. Cardiol. 40, 1761–1768 (2002)

    Article  Google Scholar 

  10. Nahrendorf, M. et al. The healing myocardium sequentially mobilizes two monocyte subsets with divergent and complementary functions. J. Exp. Med. 204, 3037–3047 (2007)

    Article  CAS  Google Scholar 

  11. Nahrendorf, M., Pittet, M. J. & Swirski, F. K. Monocytes: protagonists of infarct inflammation and repair after myocardial infarction. Circulation 121, 2437–2445 (2010)

    Article  Google Scholar 

  12. Massa, M. et al. Increased circulating hematopoietic and endothelial progenitor cells in the early phase of acute myocardial infarction. Blood 105, 199–206 (2005)

    Article  CAS  Google Scholar 

  13. Galis, Z. S., Sukhova, G. K., Lark, M. W. & Libby, P. Increased expression of matrix metalloproteinases and matrix degrading activity in vulnerable regions of human atherosclerotic plaques. J. Clin. Invest. 94, 2493–2503 (1994)

    Article  CAS  Google Scholar 

  14. Libby, P. Inflammation in atherosclerosis. Nature 420, 868–874 (2002)

    Article  ADS  CAS  Google Scholar 

  15. Chen, J. et al. In vivo imaging of proteolytic activity in atherosclerosis. Circulation 105, 2766–2771 (2002)

    Article  Google Scholar 

  16. Nahrendorf, M. et al. Hybrid in vivo FMT-CT imaging of protease activity in atherosclerosis with customized nanosensors. Arterioscler. Thromb. Vasc. Biol. 29, 1444–1451 (2009)

    Article  CAS  Google Scholar 

  17. Tacke, F. et al. Monocyte subsets differentially employ CCR2, CCR5, and CX3CR1 to accumulate within atherosclerotic plaques. J. Clin. Invest. 117, 185–194 (2007)

    Article  CAS  Google Scholar 

  18. Swirski, F. K. et al. Ly-6Chi monocytes dominate hypercholesterolemia-associated monocytosis and give rise to macrophages in atheromata. J. Clin. Invest. 117, 195–205 (2007)

    Article  CAS  Google Scholar 

  19. Robbins, C. S. et al. Extramedullary hematopoiesis generates Ly-6Chigh monocytes that infiltrate atherosclerotic lesions. Circulation 125, 364–374 (2012)

    Article  Google Scholar 

  20. Leuschner, F. et al. Rapid monocyte kinetics in acute myocardial infarction are sustained by extramedullary monocytopoiesis. J. Exp. Med. 209, 123–137 (2012)

    Article  CAS  Google Scholar 

  21. Swirski, F. K. et al. Identification of splenic reservoir monocytes and their deployment to inflammatory sites. Science 325, 612–616 (2009)

    Article  ADS  CAS  Google Scholar 

  22. Psaltis, P. J. et al. Identification of a monocyte-predisposed hierarchy of hematopoietic progenitor cells in the adventitia of postnatal murine aorta. Circulation 125, 592–603 (2012)

    Article  Google Scholar 

  23. Kondo, M. et al. Biology of hematopoietic stem cells and progenitors: implications for clinical application. Annu. Rev. Immunol. 21, 759–806 (2003)

    Article  CAS  Google Scholar 

  24. Geissmann, F. et al. Development of monocytes, macrophages, and dendritic cells. Science 327, 656–661 (2010)

    Article  ADS  CAS  Google Scholar 

  25. Zigmond, R. E. & Ben-Ari, Y. Electrical stimulation of preganglionic nerve increases tyrosine hydroxylase activity in sympathetic ganglia. Proc. Natl Acad. Sci. USA 74, 3078–3080 (1977)

    Article  ADS  CAS  Google Scholar 

  26. Katayama, Y. et al. Signals from the sympathetic nervous system regulate hematopoietic stem cell egress from bone marrow. Cell 124, 407–421 (2006)

    Article  CAS  Google Scholar 

  27. Méndez-Ferrer, S. et al. Mesenchymal and haematopoietic stem cells form a unique bone marrow niche. Nature 466, 829–834 (2010)

    Article  ADS  Google Scholar 

  28. Méndez-Ferrer, S., Lucas, D., Battista, M. & Frenette, P. S. Haematopoietic stem cell release is regulated by circadian oscillations. Nature 452, 442–447 (2008)

    Article  ADS  Google Scholar 

  29. Cannon, C. P. et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N. Engl. J. Med. 350, 1495–1504 (2004)

    Article  CAS  Google Scholar 

  30. Hoffmann, C., Leitz, M. R., Oberdorf-Maass, S., Lohse, M. J. & Klotz, K. N. Comparative pharmacology of human β-adrenergic receptor subtypes—characterization of stably transfected receptors in CHO cells. Naunyn Schmiedebergs Arch. Pharmacol. 369, 151–159 (2004)

    Article  CAS  Google Scholar 

  31. Kruszewska, B., Felten, S. Y. & Moynihan, J. A. B. Alterations in cytokine and antibody production following chemical sympathectomy in two strains of mice. J. Immunol. 155, 4613–4620 (1995)

    CAS  PubMed  Google Scholar 

  32. Lo Celso, C. et al. Live-animal tracking of individual haematopoietic stem/progenitor cells in their niche. Nature 457, 92–96 (2009)

    Article  ADS  CAS  Google Scholar 

  33. Ding, L., Saunders, T. L., Enikolopov, G. & Morrison, S. J. Endothelial and perivascular cells maintain haematopoietic stem cells. Nature 481, 457–462 (2012)

    Article  ADS  CAS  Google Scholar 

  34. Williams, D. A., Rios, M., Stephens, C. & Patel, V. P. Fibronectin and VLA-4 in haematopoietic stem cell–microenvironment interactions. Nature 352, 438–441 (1991)

    Article  ADS  CAS  Google Scholar 

  35. Lo Celso, C. & Scadden, D. T. The haematopoietic stem cell niche at a glance. J. Cell Sci. 124, 3529–3535 (2011)

    Article  CAS  Google Scholar 

  36. Libby, P. & Theroux, P. Pathophysiology of coronary artery disease. Circulation 111, 3481–3488 (2005)

    Article  Google Scholar 

Download references

Acknowledgements

We thank the CSB Mouse Imaging Program (J. Truelove, D. Jeon, J. Donahoe, B. Marinelli) and K. Naxerova for helpful discussions. This work was funded by grants from the National Institute of Health R01-HL096576, R01-HL095629 (M.N.); R01-EB006432, T32-CA79443, P50-CA086355 (R.W.). F.L. was funded in part by Deutsche Forschungsgemeinschaft SFB 938/Z2. Fig. 5e was produced using Servier Medical Art (http://www.servier.com).

Author information

Author notes

  1. Partha Dutta and Gabriel Courties: These authors contributed equally to this work.

Authors and Affiliations

  1. Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Simches Research Building, 185 Cambridge Street, Boston, Massachusetts 02114, USA,

    Partha Dutta, Gabriel Courties, Florian Leuschner, Rostic Gorbatov, Clinton S. Robbins, Yoshiko Iwamoto, Brian Thompson, Alicia L. Carlson, Timo Heidt, Maulik D. Majmudar, Martin Etzrodt, Peter Waterman, James R. Stone, Claudio Vinegoni, Mikael J. Pittet, Charles P. Lin, Filip K. Swirski, Ralph Weissleder & Matthias Nahrendorf

  2. Departments of Radiology and Neurology, Stroke and Neurovascular Regulation Laboratory, Massachusetts General Hospital/Harvard Medical School, 149 13th Street, Charlestown, Massachusetts 02129, USA,

    Ying Wei & Michael A. Moskowitz

  3. Department of Cardiology, Medical University Hospital Heidelberg, Im Neuenheimer Feld 410, D-69120 Heidelberg, Germany,

    Florian Leuschner & Hugo A. Katus

  4. Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Boston, 02115, Massachusetts, USA

    Maulik D. Majmudar & Peter Libby

  5. Institute of Pathology, University Hospital Heidelberg, Im Neuenheimer Feld 220/221, 69120 Heidelberg, Germany,

    Felix Lasitschka

  6. The Ragon Institute of MGH, MIT and Harvard at Massachusetts General Hospital, Charlestown, 02129, Massachusetts, USA

    Michael T. Waring & Adam T. Chicoine

  7. Howard Hughes Medical Institute, Chevy Chase, 20815, Maryland, USA

    Michael T. Waring & Adam T. Chicoine

  8. Department of Cardiology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, the Netherlands,

    Anja M. van der Laan & Jan J. Piek

  9. Department of Pathology and Cardiac Surgery, ICaR-VU, VU University Medical Center, De Boelelaan 1117, 1081 HV Amsterdam, the Netherlands,

    Hans W. M. Niessen

  10. Division of Vascular Surgery, Peter Munk Cardiac Centre, Toronto General Hospital, University of Toronto, Toronto, Ontario M5G-2C4, Canada,

    Barry B. Rubin

  11. Department of Pathology, Peter Munk Cardiac Centre, University of Toronto, Toronto, Ontario M5G-2C4, Canada,

    Jagdish Butany

  12. Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, 02114, Massachusetts, USA

    James R. Stone

  13. Department of Medicine, Cardiovascular Division, TIMI Study Group, Brigham and Women’s Hospital, Boston, 02145, Massachusetts, USA

    Sabina A. Murphy, David A. Morrow & Marc S. Sabatine

  14. Department of Systems Biology, Harvard Medical School, Boston, 02115, Massachusetts, USA

    Ralph Weissleder

Authors
  1. Partha Dutta
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gabriel Courties
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ying Wei
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Florian Leuschner
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Rostic Gorbatov
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Clinton S. Robbins
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yoshiko Iwamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Brian Thompson
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Alicia L. Carlson
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Timo Heidt
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Maulik D. Majmudar
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Felix Lasitschka
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Martin Etzrodt
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Peter Waterman
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Michael T. Waring
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Adam T. Chicoine
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Anja M. van der Laan
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Hans W. M. Niessen
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Jan J. Piek
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Barry B. Rubin
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Jagdish Butany
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. James R. Stone
    View author publications

    You can also search for this author in PubMed Google Scholar

  23. Hugo A. Katus
    View author publications

    You can also search for this author in PubMed Google Scholar

  24. Sabina A. Murphy
    View author publications

    You can also search for this author in PubMed Google Scholar

  25. David A. Morrow
    View author publications

    You can also search for this author in PubMed Google Scholar

  26. Marc S. Sabatine
    View author publications

    You can also search for this author in PubMed Google Scholar

  27. Claudio Vinegoni
    View author publications

    You can also search for this author in PubMed Google Scholar

  28. Michael A. Moskowitz
    View author publications

    You can also search for this author in PubMed Google Scholar

  29. Mikael J. Pittet
    View author publications

    You can also search for this author in PubMed Google Scholar

  30. Peter Libby
    View author publications

    You can also search for this author in PubMed Google Scholar

  31. Charles P. Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  32. Filip K. Swirski
    View author publications

    You can also search for this author in PubMed Google Scholar

  33. Ralph Weissleder
    View author publications

    You can also search for this author in PubMed Google Scholar

  34. Matthias Nahrendorf
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

P.D. and G.C. performed experiments, collected and analysed the data, and contributed to writing the manuscript, R.G. did surgeries and performed experiments, Y.W., F.Le., R.G., C.S.R., Y.I., B.T., A.L.C., T.H., M.D.M., F.La., M.E., P.W., M.T.W., A.T.C., A.M.v.d.L., H.W.M.N., J.J.P., B.B.R., J.B., J.R.S., H.A.K., C.V., S.A.M., D.A.M. and M.S.S. performed experiments, collected, analysed and discussed data, M.A.M., M.J.P., P.L., C.P.L., F.K.S. and R.W. conceived experiments and discussed strategy and results; M.N. designed and managed the study and wrote the manuscript, which was edited and approved by all co-authors.

Corresponding authors

Correspondence to Ralph Weissleder or Matthias Nahrendorf.

Ethics declarations

Competing interests

M.S.S., D.A.M. and S.A.M. received grant support from AstraZeneca and GSK. The remaining authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Figures 1-29, Supplementary Table 1, Supplementary Methods and Supplementary References. (PDF 5464 kb)

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Cite this article

Dutta, P., Courties, G., Wei, Y. et al. Myocardial infarction accelerates atherosclerosis. Nature 487, 325–329 (2012). https://doi.org/10.1038/nature11260

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature11260

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

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