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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 references 18

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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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            Increased expression of matrix metalloproteinases and matrix degrading activity in vulnerable regions of human atherosclerotic plaques.

             Z Galis,  P. Libby,  M Lark (1994)
            Dysregulated extracellular matrix (ECM) metabolism may contribute to vascular remodeling during the development and complication of human atherosclerotic lesions. We investigated the expression of matrix metalloproteinases (MMPs), a family of enzymes that degrade ECM components in human atherosclerotic plaques (n = 30) and in uninvolved arterial specimens (n = 11). We studied members of all three MMP classes (interstitial collagenase, MMP-1; gelatinases, MMP-2 and MMP-9; and stromelysin, MMP-3) and their endogenous inhibitors (TIMPs 1 and 2) by immunocytochemistry, zymography, and immunoprecipitation. Normal arteries stained uniformly for 72-kD gelatinase and TIMPs. In contrast, plaques' shoulders and regions of foam cell accumulation displayed locally increased expression of 92-kD gelatinase, stromelysin, and interstitial collagenase. However, the mere presence of MMP does not establish their catalytic capacity, as the zymogens lack activity, and TIMPs may block activated MMPs. All plaque extracts contained activated forms of gelatinases determined zymographically and by degradation of 3H-collagen type IV. To test directly whether atheromata actually contain active matrix-degrading enzymes in situ, we devised a method which allows the detection and microscopic localization of MMP enzymatic activity directly in tissue sections. In situ zymography revealed gelatinolytic and caseinolytic activity in frozen sections of atherosclerotic but not of uninvolved arterial tissues. The MMP inhibitors, EDTA and 1,10-phenanthroline, as well as recombinant TIMP-1, reduced these activities which colocalized with regions of increased immunoreactive MMP expression, i.e., the shoulders, core, and microvasculature of the plaques. Focal overexpression of activated MMP may promote destabilization and complication of atherosclerotic plaques and provide novel targets for therapeutic intervention.
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              Pathophysiology of coronary artery disease.

              During the past decade, our understanding of the pathophysiology of coronary artery disease (CAD) has undergone a remarkable evolution. We review here how these advances have altered our concepts of and clinical approaches to both the chronic and acute phases of CAD. Previously considered a cholesterol storage disease, we currently view atherosclerosis as an inflammatory disorder. The appreciation of arterial remodeling (compensatory enlargement) has expanded attention beyond stenoses evident by angiography to encompass the biology of nonstenotic plaques. Revascularization effectively relieves ischemia, but we now recognize the need to attend to nonobstructive lesions as well. Aggressive management of modifiable risk factors reduces cardiovascular events and should accompany appropriate revascularization. We now recognize that disruption of plaques that may not produce critical stenoses causes many acute coronary syndromes (ACS). The disrupted plaque represents a "solid-state" stimulus to thrombosis. Alterations in circulating prothrombotic or antifibrinolytic mediators in the "fluid phase" of the blood can also predispose toward ACS. Recent results have established the multiplicity of "high-risk" plaques and the widespread nature of inflammation in patients prone to develop ACS. These findings challenge our traditional view of coronary atherosclerosis as a segmental or localized disease. Thus, treatment of ACS should involve 2 overlapping phases: first, addressing the culprit lesion, and second, aiming at rapid "stabilization" of other plaques that may produce recurrent events. The concept of "interventional cardiology" must expand beyond mechanical revascularization to embrace preventive interventions that forestall future events.
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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

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                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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