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Myocardial infarction accelerates atherosclerosis

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

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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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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.

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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).

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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

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  1. Partha Dutta
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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.

Corresponding authors

Correspondence to Ralph Weissleder or Matthias Nahrendorf.

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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.

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

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

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