Boring, L., Gosling, J., Cleary, M. & Charo, I. F. Decreased lesion formation in CCR2−/− mice reveals a role for chemokines in the initiation of atherosclerosis. Nature 394, 894-897
Gladstone Institute of Cardiovascular Disease, San Francisco, California 94141, USA. Nature
(Impact Factor: 41.46).
09/1998; 394(6696):894-7. DOI: 10.1038/29788
Chemokines are proinflammatory cytokines that function in leukocyte chemoattraction and activation and have recently been shown to block the HIV-1 infection of target cells through interactions with chemokine receptors. In addition to their function in viral disease, chemokines have been implicated in the pathogenesis of atherosclerosis. Expression of the CC chemokine monocyte chemoattractant protein-1 (MCP-1) is upregulated in human atherosclerotic plaques, in arteries of primates on a hypercholesterolaemic diet; and in vascular endothelial and smooth muscle cells exposed to minimally modified lipids. To determine whether MCP-1 is causally related to the development of atherosclerosis, we generated mice that lack CCR2, the receptor for MCP-1 (ref. 7), and crossed them with apolipoprotein (apo) E-null mice which develop severe atherosclerosis. Here we show that the selective absence of CCR2 decreases lesion formation markedly in apoE-/- mice but has no effect on plasma lipid or lipoprotein concentrations. These data reveal a role for MCP-1 in the development of early atherosclerotic lesions and suggest that upregulation of this chemokine by minimally oxidized lipids is an important link between hyperlipidaemia and fatty streak formation.
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Available from: Bogusz Trojanowicz
- "These novel findings are extremely important because the motility of these cells may be boosted in an autocrine manner independently from endothelial function. The fact that MCP-1 is up-regulated in atherosclerotic plaques and arteries of animals fed a high cholesterol diet and that disruption of CCR2 in mouse models is related to anti-atherosclerotic actions , , , , , allows us to designate ACE-overexpressing monocytes as highly pro-atherogenic. "
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Elevated expression levels of monocytic-ACE have been found in haemodialysis patients. They are not only epidemiologically linked with increased mortality and cardiovascular disease, but may also directly participate in the initial steps of atherosclerosis. To further address this question we tested the role of monocytic-ACE in promotion of atherosclerotic events in vitro under conditions mimicking those of chronic renal failure.
Methods and Results
Treatment of human primary monocytes or THP-1 cells with uremic serum as well as PMA-induced differentiation led to significantly up-regulated expression of ACE, further increased by additional treatment with LPS. Functionally, these monocytes revealed significantly increased adhesion and transmigration through endothelial monolayers. Overexpression of ACE in transfected monocytes or THP-1 cells led to development of more differentiated, macrophage-like phenotype with up-regulated expression of Arg1, MCSF, MCP-1 and CCR2. Expression of pro-inflammatory cytokines TNFa and IL-6 were also noticeably up-regulated. ACE overexpression resulted in significantly increased adhesion and transmigration properties. Transcriptional screening of ACE-overexpressing monocytes revealed noticeably increased expression of Angiotensin II receptors and adhesion- as well as atherosclerosis-related ICAM-1 and VCAM1. Inhibition of monocyte ACE or AngII-receptor signalling led to decreased adhesion potential of ACE-overexpressing cells.
Taken together, these data demonstrate that uremia induced expression of monocytic-ACE mediates the development of highly pro-atherogenic cells via an AngII-dependent mechanism.
PLoS ONE 07/2014; 9(7):e102137. DOI:10.1371/journal.pone.0102137 · 3.23 Impact Factor
Available from: Holger Cynis
- "For example, isoQC – but not QC – is essential for biological activity of monocyte chemoattractant protein-1 (MCP-1; also called CCL2) in vivo by catalyzing the formation of N-terminal pGlu, which also confers resistance against aminopeptidase degradation (van Coillie et al., 1998; Cynis et al., 2011). CCL2 controls infiltration of monocytes into inflamed tissue and plays a pivotal role in several inflammatory disorders, such as atherosclerosis (Boring et al., 1998; Gosling et al., 1999; Mori et al., 2002), cancer (Fridlender et al., 2010), pancreatitis (Marra, 2005), Alzheimer's disease (Galimberti et al., 2006; Sokolova et al., 2009) or multiple sclerosis (Gerard and Rollins, 2001). Together, inhibition of QCs may have therapeutic potential to treat disorders associated with protein aggregation and (neuro)inflammation. "
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ABSTRACT: Glutaminyl cyclases (QCs) catalyze the formation of pyroglutamate (pGlu) from glutamine precursors at the N-terminus of a number of peptide hormones, neuropeptides and chemokines. This post-translational modification stabilizes these peptides, protects them from proteolytical degradation or is important for their biological activity. However, QC is also involved in a pathogenic pGlu modification of peptides accumulating in protein aggregation disorders such as Alzheimer's disease and familial Danish and familial British dementia. Its isoenzyme (isoQC) was shown to contribute to aspects of inflammation by pGlu-modifying and thereby stabilizing the monocyte chemoattractant protein CCL2. For the generation of respective animal models and for pharmacological treatment studies the characterization of the mouse strain and brain region-specific expression of QC and isoQC is indispensible. In order to address this issue, we used enzymatic activity assays and specific antibodies to detect both QC variants by immunohistochemistry in nine different mouse strains. Comparing different brain regions, the highest enzymatic QC/isoQC activity was detected in ventral brain, followed by cortex and hippocampus. Immunohistochemical stainings revealed that QC/isoQC activity in cortex mostly arises from isoQC expression. For most brain regions, the highest QC/isoQC activity was detected in C3H and FVB mice, whereas low QC/isoQC activity was present in CD1, SJL and C57 mice. Quantification of QC- and isoQC-immunoreactive cells by unbiased stereology revealed a higher abundance of isoQC- than of QC-immunoreactive neurons in Edinger-Westphal nucleus and in substantia nigra. In the locus coeruleus, however, there were comparable densities of QC- and of isoQC-immunoreactive neurons. These observations are of considerable importance with regard to the selection of appropriate mouse strains for the study of QC/isoQC relevance in mouse models of neurodegeneration and neuroinflammation and for the testing of therapeutical interventions in these models.
International Journal of Developmental Neuroscience 05/2014; DOI:10.1016/j.ijdevneu.2014.05.008 · 2.58 Impact Factor
Available from: Oana Herlea-Pana
- "Several chemokines including CCL2, CCL5, and CX3CL1 as well as their cognate chemokine receptors CCR2, CCR5, and CX3CR1 are expressed in mouse and human atherosclerotic lesions [39– 44]. Proatherogenic ApoE −/− and Ldlr −/− strains fed the Western diet (21% fat, 0.3% cholesterol) that are deficient in CCL2  or CCR2   show reduced atherosclerosis burden compared to wild-type controls. Single nucleotide polymorphisms (SNPs) in the promoter of CCL2, CCL2- 2518G , and in the open reading frame of CCR2, CCR2- V64I , have been associated with increased risk of myocardial infarction in humans. "
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ABSTRACT: The escalating epidemic of obesity has increased the incidence of obesity-induced complications to historically high levels. Adipose tissue is a dynamic energy depot, which stores energy and mobilizes it during nutrient deficiency. Excess nutrient intake resulting in adipose tissue expansion triggers lipid release and aberrant adipokine, cytokine and chemokine production, and signaling that ultimately lead to adipose tissue inflammation, a hallmark of obesity. This low-grade chronic inflammation is thought to link obesity to insulin resistance and the associated comorbidities of metabolic syndrome such as dyslipidemia and hypertension, which increase risk of type 2 diabetes and cardiovascular disease. In this review, we focus on and discuss members of the chemokine system for which there is clear evidence of participation in the development of obesity and obesity-induced pathologies.
Journal of Immunology Research 03/2014; 2014(1):181450. DOI:10.1155/2014/181450 · 2.93 Impact Factor
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