CCL2/Monocyte Chemoattractant Protein-1 Regulates Inflammatory Responses Critical to Healing Myocardial Infarcts

Dewald, Oliver; Zymek, Paweł; Winkelmann, Kim; Koerting, Anna; Ren, Guofeng; Abou-Khamis, Tareq; Michael, Lloyd H.; Rollins, Barrett J.; Entman, Mark L.; Frangogiannis, Nikolaos G.

doi:10.1161/01.res.0000163017.13772.3a

Cited by 623 publications

(550 citation statements)

References 38 publications

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“…Despite showing delayed phagocytotic removal of dead cardiomyocytes, MCP-1 −/− mice had attenuated left ventricular remodeling, but similar infarct size when compared with wildtype animals. MCP-1 antibody inhibition resulted in defects comparable with the pathological findings noted in infarcted MCP-1 −/− animals without an effect on macrophage recruitment [128].…”

Section: Chemokines In Myocardial Infarctionmentioning

confidence: 59%

“…Studies from our laboratory demonstrated that MCP-1 −/− mice had decreased and delayed macrophage infiltration in the healing infarct and exhibited delayed replacement of injured cardiomyocytes with granulation tissue. MCP-1 −/− infarcts had decreased mRNA expression of the cytokines TNF-α, IL-1β, Transforming Growth Factor (TGF)-β, and IL-10 and showed defective macrophage differentiation [128]. MCP-1 deficiency diminished myofibroblast accumulation but did not significantly affect infarct angiogenesis.…”

Section: Chemokines In Myocardial Infarctionmentioning

confidence: 99%

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The immune system and cardiac repair

Frangogiannis

2008

Pharmacological Research

572

499

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Myocardial infarction is the most common cause of cardiac injury and results in acute loss of a large number of myocardial cells. Because the heart has negligible regenerative capacity, cardiomyocyte death triggers a reparative response that ultimately results in formation of a scar and is associated with dilative remodeling of the ventricle. Cardiac injury activates innate immune mechanisms initiating an inflammatory reaction. Toll Like Receptor-mediated pathways, the complement cascade and reactive oxygen generation induce Nuclear Factor (NF)-κB activation and upregulate chemokine and cytokine synthesis in the infarcted heart. Chemokines stimulate the chemotactic recruitment of inflammatory leukocytes into the infarct, while cytokines promote adhesive interactions between leukocytes and endothelial cells, resulting in transmigration of inflammatory cells into the site of injury. Monocyte subsets play distinct roles in phagocytosis of dead cardiomyocytes and in granulation tissue formation through the release of growth factors. Clearance of dead cells and matrix debris may be essential for resolution of inflammation and transition into the reparative phase. Transforming Growth Factor (TGF)-β plays a crucial role in cardiac repair by suppressing inflammation while promoting myofibroblast phenotypic modulation and extracellular matrix deposition. Myofibroblast proliferation and angiogenesis result in formation of highly vascularized granulation tissue. As the healing infarct matures, fibroblasts become apoptotic and a collagen-based matrix is formed, while many infarct neovessels acquire a muscular coat and uncoated vessels regress. Timely resolution of the inflammatory infiltrate and spatial containment of the inflammatory and reparative response into the infarcted area are essential for optimal infarct healing. Targeting inflammatory pathways following infarction may reduce cardiomyocyte injury and attenuate adverse remodeling. In addition, understanding the role of the immune system in cardiac repair is necessary in order to design optimal strategies for cardiac regeneration.

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Section: Chemokines In Myocardial Infarctionmentioning

confidence: 59%

Section: Chemokines In Myocardial Infarctionmentioning

confidence: 99%

The immune system and cardiac repair

Frangogiannis

2008

Pharmacological Research

572

499

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“…injection of sodium pentobarbital (60 g/g). A closed-chest mouse model of reperfused myocardial infarction was used to avoid the confounding effects of surgical trauma and inflammation, which may influence the baseline levels of chemokines and cytokines (2). The left anterior descending coronary artery was occluded for 1 h then reperfused for 6 h to 7 days.…”

Section: Murine Ischemia/reperfusion Protocolsmentioning

confidence: 99%

“…P ostinfarction cardiac repair is dependent on release of inflammatory mediators and subsequent infiltration of the infarcted myocardium with leukocytes that clear the wound from dead cells and matrix debris (1)(2)(3). However, optimal infarct healing requires timely activation of "stop signals" that suppress chemokine and cytokine synthesis resulting in resolution of the inflammatory infiltrate.…”

mentioning

confidence: 99%

CD44 Is Critically Involved in Infarct Healing by Regulating the Inflammatory and Fibrotic Response

Huebener

Abou-Khamis

Zymek

et al. 2008

The Journal of Immunology

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164

151

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Infarct healing is dependent on an inflammatory reaction that results in leukocyte infiltration and clearance of the wound from dead cells and matrix debris. However, optimal infarct healing requires timely activation of “stop signals” that suppress inflammatory mediator synthesis and mediate resolution of the inflammatory infiltrate, promoting formation of a scar. A growing body of evidence suggests that interactions involving the transmembrane receptor CD44 may play an important role in resolution of inflammation and migration of fibroblasts in injured tissues. We examined the role of CD44 signaling in infarct healing and cardiac remodeling using a mouse model of reperfused infarction. CD44 expression was markedly induced in the infarcted myocardium and was localized on infiltrating leukocytes, wound myofibroblasts, and vascular cells. In comparison with wild-type mice, CD44−/− animals showed enhanced and prolonged neutrophil and macrophage infiltration and increased expression of proinflammatory cytokines following myocardial infarction. In CD44null infarcts, the enhanced inflammatory phase was followed by decreased fibroblast infiltration, reduced collagen deposition, and diminished proliferative activity. Isolated CD44null cardiac fibroblasts had reduced proliferation upon stimulation with serum and decreased collagen synthesis in response to TGF-β in comparison to wild-type fibroblasts. The healing defects in CD44−/− mice were associated with enhanced dilative remodeling of the infarcted ventricle, without affecting the size of the infarct. Our findings suggest that CD44-mediated interactions are critically involved in infarct healing. CD44 signaling is important for resolution of the postinfarction inflammatory reaction and regulates fibroblast function.

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“…[2][3][4][5][6][7] In other settings, CCL2 appears to be beneficial as it protects against initial HIV infection, is neuroprotective against HIV Tat and N-methyl-D-aspartate-induced apoptosis during early HIV infection, and promotes healing following myocardial infarct. [8][9][10] Genetic analysis of the distal CCL2 promoter revealed a polymorphism at À2578 (alternatively designated À2518 11 ) with functional consequences in the context of a luciferase reporter assay. Specifically, CCL2 distal promoters that harbor the À2578 G allele exhibit higher levels of activity than those harboring the A allele in interleukin (IL)-1b-stimulated cells.…”

Section: Introductionmentioning

confidence: 99%