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      Myocardial infarction accelerates atherosclerosis

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          SUMMARY

          During progression of atherosclerosis, myeloid cells destabilize lipid-rich plaque in the arterial wall and cause its 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 ischemic 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. When seeking the source of surplus monocytes in plaque, we found that myocardial infarction liberated hematopoietic stem and progenitor cells from bone marrow niches via sympathetic nervous system signaling. 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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          Most cited references38

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          Development of monocytes, macrophages, and dendritic cells.

          Monocytes and macrophages are critical effectors and regulators of inflammation and the innate immune response, the immediate arm of the immune system. Dendritic cells initiate and regulate the highly pathogen-specific adaptive immune responses and are central to the development of immunologic memory and tolerance. Recent in vivo experimental approaches in the mouse have unveiled new aspects of the developmental and lineage relationships among these cell populations. Despite this, the origin and differentiation cues for many tissue macrophages, monocytes, and dendritic cell subsets in mice, and the corresponding cell populations in humans, remain to be elucidated.
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            Progress and challenges in translating the biology of atherosclerosis.

            Atherosclerosis is a chronic disease of the arterial wall, and a leading cause of death and loss of productive life years worldwide. Research into the disease has led to many compelling hypotheses about the pathophysiology of atherosclerotic lesion formation and of complications such as myocardial infarction and stroke. Yet, despite these advances, we still lack definitive evidence to show that processes such as lipoprotein oxidation, inflammation and immunity have a crucial involvement in human atherosclerosis. Experimental atherosclerosis in animals furnishes an important research tool, but extrapolation to humans requires care. Understanding how to combine experimental and clinical science will provide further insight into atherosclerosis and could lead to new clinical applications.
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              Inflammation in atherosclerosis.

              Abundant data link hypercholesterolaemia to atherogenesis. However, only recently have we appreciated that inflammatory mechanisms couple dyslipidaemia to atheroma formation. Leukocyte recruitment and expression of pro-inflammatory cytokines characterize early atherogenesis, and malfunction of inflammatory mediators mutes atheroma formation in mice. Moreover, inflammatory pathways promote thrombosis, a late and dreaded complication of atherosclerosis responsible for myocardial infarctions and most strokes. The new appreciation of the role of inflammation in atherosclerosis provides a mechanistic framework for understanding the clinical benefits of lipid-lowering therapies. Identifying the triggers for inflammation and unravelling the details of inflammatory pathways may eventually furnish new therapeutic targets.
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                Author and article information

                Journal
                0410462
                6011
                Nature
                Nature
                Nature
                0028-0836
                1476-4687
                30 May 2012
                19 July 2012
                19 January 2013
                : 487
                : 7407
                : 325-329
                Affiliations
                [1 ]Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Simches Research Building, 185 Cambridge St., Boston, MA 02114, USA
                [2 ]Stroke and Neurovascular Regulation Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital/Harvard Medical School, 149 13 th Street, Charlestown, MA 02129
                [3 ]Department of Cardiology, Medical University Hospital Heidelberg, Im Neuenheimer Feld 410, D-69120 Heidelberg, Germany
                [4 ]Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA
                [5 ]Institute of Pathology, University Hospital Heidelberg, Im Neuenheimer Feld 220/221, 69120 Heidelberg, Germany; Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA
                [6 ]The Ragon Institute of MGH, MIT and Harvard at Massachusetts General Hospital, Charlestown, MA 02129, USA
                [7 ]Howard Hughes Medical Institute, Chevy Chase, Maryland, USA
                [8 ]Department of Cardiology, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands
                [9 ]Department of Pathology and Cardiac Surgery, ICaR-VU, VU University Medical Center, Amsterdam, Netherlands
                [10 ]Division of Vascular Surgery, Peter Munk Cardiac Centre, Toronto General Hospital, University Health Network, Toronto, Ontario M5G-2C4, Canada
                [11 ]Division of Pathology, Peter Munk Cardiac Centre, Toronto General Hospital, University Health Network, Toronto, Ontario M5G-2C4, Canada
                [12 ]TIMI Study Group, Cardiovascular Division, Brigham and Women’s Hospital, Boston, MA
                [13 ]Department of Systems Biology, Harvard Medical School, Boston, MA
                Author notes
                Corresponding authors: Matthias Nahrendorf, Filip K. Swirski, Ralph Weissleder, Center for Systems Biology, 185 Cambridge Street, Boston, MA 02114, Tel: (617) 643-0500, Fax: (617) 643-6133, mnahrendorf@ 123456mgh.harvard.edu fswirski@ 123456mgh.harvard.edu rweissleder@ 123456mgh.harvard.edu
                [*]

                These authors contributed equally to this work

                Article
                NIHMS380684
                10.1038/nature11260
                3401326
                22763456
                1c851b4a-3a65-414a-8e7b-bc87702b4056

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                History
                Funding
                Funded by: National Cancer Institute : NCI
                Award ID: T32 CA079443 || CA
                Funded by: National Heart, Lung, and Blood Institute : NHLBI
                Award ID: R01 HL096576 || HL
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