Mast cells in atherosclerosis

Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, Leiden University, Leiden, The Netherlands.
Thrombosis and Haemostasis (Impact Factor: 4.98). 08/2011; 106(5):820-6. DOI: 10.1160/TH11-05-0291
Source: PubMed


The mast cell, a potent inflammatory cell type, is widely distributed over several tissues, but particularly prominent at the interface exposed to the environment to act in the first line of defense against pathogens. Upon activation mast cells release granules, which contain a large panel of mediators, including neutral proteases (e.g. chymase and tryptase), cathepsins, heparin, histamine and a variety of cytokines and growth factors. While mast cells have been demonstrated to be critically involved in a number of Th2 dominated diseases such as asthma and allergy, recent investigations have now also implicated mast cells in the pathogenesis of atherosclerosis and acute cardiovascular syndromes. In this review, we will discuss the contribution of mast cells to the initiation and progression of atherosclerosis and gauge the therapeutic opportunities of mast cell targeted intervention in acute cardiovascular syndromes.

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    • "Due to the increased expression of endothelial E-selectin, the synergistic effect of TNF-α and histamine on monocyte-endothelium adhesion becomes particularly strong under shear flow conditions. Mast cells have been recognized as a key player in advanced atherosclerosis [62, 63] , and recent in vivo studies show that they also are important in atherogenesis [64]. However, the mechanism by which they become involved in this process is not established. "
    [Show abstract] [Hide abstract] ABSTRACT: Oxidized low-density lipoprotein (OxLDL) is a risk factor for atherosclerosis, due to its role in endothelial dysfunction and foam cell formation. Tissue-resident cells such as macro-phages and mast cells release inflammatory mediators upon activation that in turn cause endothelial activation and monocyte adhesion. Two of these mediators are tumor necrosis factor (TNF)-α, produced by macrophages, and histamine, produced by mast cells. Static and microfluidic flow experiments were conducted to determine the number of adherent monocytes on vascular endothelium activated by supernatants of oxLDL-treated macro-phages and mast cells or directly by oxLDL. The expression of adhesion molecules on activated endothelial cells and the concentration of TNF-α and histamine in the supernatants were measured by flow cytometry and enzyme-linked immunosorbent assay, respectively. A low dose of oxLDL (8 μg/ml), below the threshold for the clinical presentation of coronary artery disease, was sufficient to activate both macrophages and mast cells and synergisti-cally increase monocyte-endothelium adhesion via released TNF-α and histamine. The direct exposure of endothelial cells to a much higher dose of oxLDL (80 μg/ml) had less effect on monocyte adhesion than the indirect activation via oxLDL-treated macrophages and mast cells. The results of this work indicate that the co-activation of macrophages and mast cells by oxLDL is an important mechanism for the endothelial dysfunction and atherogene-sis. The observed synergistic effect suggests that both macrophages and mast cells play a significant role in early stages of atherosclerosis. Allergic patients with a lipid-rich diet may be at high risk for cardiovascular events due to high concentration of low-density lipoprotein and histamine in arterial vessel walls.
    Full-text · Article · Mar 2015 · PLoS ONE
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    • "In this respect, it is of interest that eosinophilic infiltration was found in case of instent restenosis, and eosinophils have been identified as important modulators of restenosis after stent implantation [31] [32]. Recent findings have also implicated mast cells in the pathogenesis of cardiovascular disorders [33]. Therefore, it is possible to hypothesize that IL-33, released by stromal cells such as endothelial and smooth muscle cells during damage or injury, via activation of different immune cells might play an important role in the process of restenosis. "
    [Show abstract] [Hide abstract] ABSTRACT: The study aim was to determine the predictive value of interleukin (IL)-33, a recently described member of the IL-1 family of cytokines, for the development of in-stent restenosis (ISR). IL-33 serum levels were measured in 387 consecutive patients undergoing percutaneous coronary intervention (PCI) of whom 193 had stable angina, 93 non-ST elevation myocardial infarction (NSTEMI), and 101 ST-elevation MI (STEMI), respectively. Blood was taken directly before and 24 h after stent implantation. The presence of ISR was initially evaluated by clinical means after six to eight months. When presence of myocardial ischemia was suspected, coronary angiography was performed to confirm the suspected diagnosis of ISR. Clinical ISR was present in total in 34 patients (8.8%). IL-33 was detectable in 185 patients and was below detection limit in 202 patients. In patients with decreased IL-33 (n = 95), unchanged or non-detectable levels (n = 210) or increased levels of IL-33 after PCI (n = 82), ISR-rate was 2.1%, 9.5% and 14.6%, respectively (p < 0.05). Accordingly, patients with ISR showed a significant increase of IL-33 upon PCI (p < 0.05). This association was independent from clinical presentation and risk factors as well as numbers and type of stents. In patients with both stable and unstable coronary artery disease, an increase of IL-33 serum levels after stent implantation is associated with a higher rate of in-stent restenosis.
    Full-text · Article · Jun 2014 · Cytokine
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    • "Mast cells (MCs) contribute importantly to the pathogenesis of atherosclerosis and abdominal aortic aneurysms (AAAs) (Kovanen, 2007; Sun et al, 2007a,b; Bot & Biessen, 2011; Swedenborg et al, 2011). After activation, MCs release pro-inflammatory cytokines (e.g. "
    [Show abstract] [Hide abstract] ABSTRACT: Immunoglobulin E (IgE) activates mast cells (MCs). It remains unknown whether IgE also activates other inflammatory cells, and contributes to the pathogenesis of abdominal aortic aneurysms (AAAs). This study demonstrates that CD4+ T cells express IgE receptor FcεR1, at much higher levels than do CD8+ T cells. IgE induces CD4+ T-cell production of IL6 and IFN-γ, but reduces their production of IL10. FcεR1 deficiency (Fcer1a−/−) protects apolipoprotein E-deficient (Apoe−/−) mice from angiotensin-II infusion-induced AAAs and reduces plasma IL6 levels. Adoptive transfer of CD4+ T cells (but not CD8+ T cells), MCs, and macrophages from Apoe−/− mice, but not those from Apoe−/− Fcer1a−/− mice, increases AAA size and plasma IL6 in Apoe−/− Fcer1a−/− recipient mice. Biweekly intravenous administration of an anti-IgE monoclonal antibody ablated plasma IgE and reduced AAAs in Apoe−/− mice. Patients with AAAs had significantly higher plasma IgE levels than those without AAAs. This study establishes an important role of IgE in AAA pathogenesis by activating CD4+ T cells, MCs, and macrophages and supports consideration of neutralizing plasma IgE in the therapeutics of human AAAs.
    Full-text · Article · Jun 2014 · EMBO Molecular Medicine
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