Roles and Relationship of Macrophages and Monocyte Chemotactic and Activating Factor/Monocyte Chemoattractant Protein-1 in the Ischemic and Reperfused Rat Heart

Kakio, Tadashi; Matsumori, Akira; Ono, Koh; Ito, Haruyasu; Matsushima, Kouji; Sasayama, Shígetake

doi:10.1038/labinvest.3780119

Cited by 86 publications

(73 citation statements)

References 21 publications

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“…In addition to its critical role in mononuclear cell recruitment, MCP-1 exerts important actions on nonhematopoietic cells, inducing angiogenic and arteriogenic effects [122] and modulating fibroblast phenotype and activity by increasing collagen expression and by regulating MMP synthesis [123]. MCP-1 upregulation has been demonstrated in a canine [124], a rat [125,126] and a mouse model [127] of experimental myocardial infarction. 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.…”

Section: Chemokines In Myocardial Infarctionmentioning

confidence: 99%

The immune system and cardiac repair

Frangogiannis

2008

Pharmacological Research

568

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: 99%

The immune system and cardiac repair

Frangogiannis

2008

Pharmacological Research

568

499

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“…MCP-1 may also contribute to complications after MI, including acute reperfusion injury 26 and chronic ventricular remodeling and heart failure. 27,28 Within 1 hour after ischemia-reperfusion, MCP-1 gene expression is increased in the infarct territory.…”

Section: Pathophysiological Implicationsmentioning

confidence: 99%

Association Between Plasma Levels of Monocyte Chemoattractant Protein-1 and Long-Term Clinical Outcomes in Patients With Acute Coronary Syndromes

et al. 2003

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Background-Monocyte chemoattractant protein-1 (MCP-1) is a chemokine responsible for the recruitment of monocytes to sites of inflammation. MCP-1 appears to play a critical role at multiple stages in atherosclerosis, including the initiation of the fatty streak, promotion of plaque instability, and remodeling after myocardial infarction. After adjustment for differences in baseline characteristics, ECG changes, troponin I, and C-reactive protein, an MCP-1 level Ͼ75th percentile (corresponding to the 90th percentile in the healthy volunteers) was associated with an increased risk of death or myocardial infarction through 10 months of follow-up (adjusted hazard ratio, 1.53; 95% CI, 1.09 to 2.14; Pϭ0.01). Conclusions-In a large cohort of patients with acute coronary syndromes, an elevated baseline level of MCP-1 was associated both with traditional risk factors for atherosclerosis as well as an increased risk for death or myocardial infarction, independent of baseline variables. Because it appears to play a crucial role at multiple stages of atherosclerosis, MCP-1 is attractive as a surrogate biomarker and merits further study as a potential therapeutic target.

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“…MCP-1 synthesis is upregulated in patients with dilated cardiomyopathy, 42,43 experimental models of heart failure, 44 and after experimental myocardial infarction. 45,46 Targeted expression of the MCP-1 gene in murine cardiac muscle induced marked macrophage infiltration, leading to depressed contractile function, hypertrophy, dilation, and myocardial fibrosis. 47 In addition to its potent mononuclear cell chemotactic activity, MCP-1 may directly mediate fibrosis through stimulation of fibroblast collagen and transforming growth factor-␤ expression.…”

Section: Recovering Myocardial Segments Demonstrate Mcp-1 Expression mentioning

confidence: 99%

Evidence for an Active Inflammatory Process in the Hibernating Human Myocardium

Frangogiannis

Shimoni

Chang

et al. 2002

The American Journal of Pathology

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Myocardial hibernation refers to a state of prolonged impairment of left ventricular function in the presence of coronary artery disease, which may be reversed by revascularization. In this study we present evidence for a local inflammatory reaction in hibernating myocardial segments from patients undergoing coronary revascularization. We obtained transmural myocardial biopsies guided by transesophageal echocardiography from patients with ischemic ventricular dysfunction undergoing bypass surgery. Among the 28 biopsied segments included in the study, 23 showed evidence of systolic dysfunction. The majority of dysfunctional segments (85.7%) were viable ( 201 Tl uptake > 60%). The samples were stained with markers for mast cells, mature resident macrophages, and the monoclonal antibody Mac387 that labels newly recruited myeloid cells. Dysfunctional segments showed more extensive fibrosis and higher macrophage density than normal segments. Among the 23 dysfunctional segments, 12 recovered function as assessed with echocardiograms 3 months after revascularization. Segments with postoperative functional recovery had comparable macrophage and mast cell density with those showing persistent dysfunction. However, biopsied segments that subsequently recovered function contained significantly higher numbers of newly recruited Mac387-positive leukocytes (18.7 ؎ 3.1 cells/mm 2 , n ‫؍‬ 12 versus 8.6 ؎ 0.9 cells/mm 2 , n ‫؍‬ 11; P ‫؍‬ 0.009). In addition, monocyte chemotactic protein-1, a potent mononuclear cell chemoattractant, was predominantly expressed in segments with recovery of function. Myocardial hibernation is associated with an inflammatory response leading to active leukocyte recruitment. Dysfunctional myocardial segments that show an active inflammatory reaction have a greater potential for recovery of function after revascularization. We pos-

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Roles and Relationship of Macrophages and Monocyte Chemotactic and Activating Factor/Monocyte Chemoattractant Protein-1 in the Ischemic and Reperfused Rat Heart

Cited by 86 publications

References 21 publications

The immune system and cardiac repair

The immune system and cardiac repair

Association Between Plasma Levels of Monocyte Chemoattractant Protein-1 and Long-Term Clinical Outcomes in Patients With Acute Coronary Syndromes

Evidence for an Active Inflammatory Process in the Hibernating Human Myocardium

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