Implication of natural killer T cells in atherosclerosis development during a LPS‐induced chronic inflammation

Ostos, Maria A.; Recalde, D.; Zakin, Mario M.; Scott‐Algara, Daniel

doi:10.1016/s0014-5793(02)02692-3

Cited by 151 publications

(130 citation statements)

References 28 publications

(25 reference statements)

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“…Higher than normal endotoxin levels are associated with a threefold higher risk of developing atherosclerosis (108). Moreover, endotoxemia enhances formation and progression of early atherosclerotic lesions in a mouse model (109). This suggests that a "chronic" gram negative infection that causes endotoxemia could potentially aggravate the atherosclerotic process.…”

Section: Cardiovascular Diseasementioning

confidence: 99%

Diabetic complications and dysregulated innate immunity

Graves

Kayal²

2008

Front Biosci

225

188

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Diabetes mellitus is a metabolic disorder that leads to the development of a number of complications. The etiology of each diabetic complication is undoubtedly multifactorial. We will focus on one potential component that may be common in many diabetic complications, dysregulation of innate immunity associated with an increased inflammatory response. High glucose levels lead to shunting through the polyol pathway, an increase in diacylglycerol which activates protein kinase C, an increase in the release of electrons that react with oxygen molecules to form superoxides, and the non-enzymatic glycosylation of proteins that result in greater formation of advanced glycation end products. Each of these can lead to aberrant cell signalling that affects innate immunity for example, by activating the MAP kinase pathway or inducing activation of transcription factors such as NF-kappaB. This may be a common feature of several complications including periodontal disease, atherosclerosis, nephropathy, impaired healing and retinopathy. These complications are frequently associated with increased expression of inflammatory cytokines such as TNF-alpha, IL-1beta and IL-6 and enhanced generation of reactive oxygen species. Cause and effect relationship between dysregulation of key components of innate immunity and diabetic complications in many instances have been demonstrated with the use of cytokine blockers and antioxidants.

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Section: Cardiovascular Diseasementioning

confidence: 99%

Diabetic complications and dysregulated innate immunity

Graves

Kayal²

2008

Front Biosci

225

188

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“…14 In vivo studies have also documented an increase in atherosclerotic lesion size with LPS administration. 15 During the course of lipid accumulation, fatty acids present in macrophages associate with cytoplasmic fatty acid-binding proteins (FABPs) for intracellular transport. 16 The adipocyte FABP (aP2; also known as FABP4) is a marker of terminal adipocyte differentiation and is under transcriptional regulation by fatty acids in these cells.…”

mentioning

confidence: 99%

Adipocyte Fatty Acid–Binding Protein Expression and Lipid Accumulation Are Increased During Activation of Murine Macrophages by Toll-Like Receptor Agonists

Kazemi

McDonald

Shigenaga

et al. 2005

ATVB

135

101

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Objective-Toll-like receptors (TLRs) recognize pathogens and mediate signaling pathways important for host defense.Recent studies implicate TLR polymorphisms in atherosclerosis risk in humans. Adipocyte fatty acid-binding protein (aP2) is present in macrophages and has an important role in atherosclerotic plaque development. We investigated aP2 expression in RAW 264.7 cells treated with lipopolysaccharide (LPS) and other TLR agonists and assessed lipid accumulation in these activated murine macrophages. Methods and Results-Stimulation with LPS, a TLR4 ligand, resulted in a 56-fold increase in aP2 mRNA expression, and zymosan, a TLR2 ligand, induced an Ϸ1500-fold increase. Polyinosine: polycytidylic acid (poly I:C), a TLR3 ligand, led to a 9-fold increase. Levels of aP2 protein were significantly increased in LPS or zymosan-treated macrophages compared with control or poly I:C-treated cells. In addition, the cholesteryl ester content of LPS or zymosan-treated macrophages was Ϸ5-fold greater in the presence of low-density lipoprotein, and triglyceride content was Ϸ2-fold greater in the absence of exogenous lipid than control or poly I:C-treated cells. Conclusions-Expression

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“…Their ligands include pathogen-associated molecular patterns such as lipopolysaccharide (LPS), a gram-negative endotoxin. 1 LPS is known to stimulate monocytes, macrophages, and neutrophils through the activation of transcription factors resulting in increased proinflammatory responses, 2,3 associated with release of cytokines and other soluble mediators. As such, infectious agents that create a heightened state of the inflammatory response are likely to directly stimulate the endothelial lining of blood vessels.…”

mentioning

confidence: 99%

Cyclophilin A as a Novel Biphasic Mediator of Endothelial Activation and Dysfunction

Kim¹,

Lessner²,

Sakurai³

et al. 2004

The American Journal of Pathology

113

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Inflammation-mediated endothelial cell (EC) dysfunction likely contributes to the pathogenesis of several vascular diseases including atherosclerosis. We found that stimulation of human umbilical vein ECs with lipopolysaccharide induced secretion of cyclophilin (CyPA) an intracellular protein belonging to the immunophilin family. We then found that when added exogenously CyPA has direct effects on ECs in vitro. At low concentrations (10 to 100 ng/ml) CyPA increased EC proliferation, migration, invasive capacity, and tubulogenesis. Gelatin zymography indicated increased secretion of active matrix metalloproteinase-2, a mediator of cell migration and angiogenesis. At high concentrations (eg, 2 g/ml) CyPA had opposite effects, decreasing EC migration and viability, possibly in relation to induction of Toll-like receptor-4 expression, detected by immunocytochemistry and flow cytometry. In vivo CyPA expression was not detectable in the luminal ECs of normal mouse carotid arteries but was rapidly induced after systemic lipopolysaccharide injection. In an experimental mouse model of atherosclerosis, CyPA expression was detected in the ECs of neocapillaries of carotid artery lesions, supporting its association with pathological angiogenesis suggested by our in vitro results. In conclusion, we found that CyPA has a biphasic activity on ECs in vitro and is up-regulated in vivo in ECs under pathological states. Our results suggest that CyPA is a novel paracrine and autocrine modulator of EC functions in immune-mediated vascular disease.

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Implication of natural killer T cells in atherosclerosis development during a LPS‐induced chronic inflammation

Cited by 151 publications

References 28 publications

Diabetic complications and dysregulated innate immunity

Diabetic complications and dysregulated innate immunity

Adipocyte Fatty Acid–Binding Protein Expression and Lipid Accumulation Are Increased During Activation of Murine Macrophages by Toll-Like Receptor Agonists

Cyclophilin A as a Novel Biphasic Mediator of Endothelial Activation and Dysfunction

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