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.

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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

    • Partha Dutta
    •  & Gabriel Courties

    These authors contributed equally to this work.

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. Stroke and Neurovascular Regulation Laboratory, Departments of Radiology and Neurology, 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, Massachusetts 02115, 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, Massachusetts 02129, USA

    • Michael T. Waring
    •  & Adam T. Chicoine
  7. Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, 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, Massachusetts 02114, USA

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

    • Sabina A. Murphy
    • , David A. Morrow
    •  & Marc S. Sabatine
  14. Department of Systems Biology, Harvard Medical School, Boston, Massachusetts 02115, USA

    • Ralph Weissleder

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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.

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.

Corresponding authors

Correspondence to Ralph Weissleder or Matthias Nahrendorf.

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    Supplementary Information

    This file contains Supplementary Figures 1-29, Supplementary Table 1, Supplementary Methods and Supplementary References.

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DOI

https://doi.org/10.1038/nature11260

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