Article

Toll-like receptor 4 is involved in outward arterial remodeling.

Experimental Cardiology Laboratory, University Medical Center, Room G02-523, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands.
Circulation (impact factor: 14.74). 02/2004; 109(3):393-8. DOI:10.1161/01.CIR.0000109140.51366.72 pp.393-8
Source: PubMed

ABSTRACT Toll-like receptor 4 (Tlr4) is the receptor for exogenous lipopolysaccharides (LPS). Expression of endogenous Tlr4 ligands, heat shock protein 60 (Hsp60) and extra domain A of fibronectin, has been observed in arthritic and oncological specimens in which matrix turnover is an important feature. In atherosclerosis, outward remodeling is characterized by matrix turnover and a structural change in arterial circumference and is associated with a vulnerable plaque phenotype. Since Tlr4 ligands are expressed during matrix turnover, we hypothesized that Tlr4 is involved in arterial remodeling.
In a femoral artery cuff model in the atherosclerotic ApoE3 (Leiden) transgenic mouse, Tlr4 activation by LPS stimulated plaque formation and subsequent outward arterial remodeling. With the use of the same model in wild-type mice, neointima formation and outward remodeling occurred. In Tlr4-deficient mice, however, no outward arterial remodeling was observed independent of neointima formation. Carotid artery ligation in wild-type mice resulted in outward remodeling without neointima formation in the contralateral artery. This was associated with an increase in Tlr4 expression and EDA and Hsp60 mRNA levels. In contrast, outward remodeling was not observed after carotid ligation in Tlr4-deficient mice.
These findings provide genetic evidence that Tlr4 is involved in outward arterial remodeling, probably through upregulation of Tlr4 and Tlr4 ligands.

0 0
 · 
0 Bookmarks
 · 
27 Views
  • Source
    Article: Genome-wide mRNA expression analysis of hepatic adaptation to high-fat diets reveals switch from an inflammatory to steatotic transcriptional program.
    Marijana Radonjic, Jorn R de Haan, Marjan J van Erk, Ko Willems van Dijk, Sjoerd A A van den Berg, Philip J de Groot, Michael Müller, Ben van Ommen
    [show abstract] [hide abstract]
    ABSTRACT: Excessive exposure to dietary fats is an important factor in the initiation of obesity and metabolic syndrome associated pathologies. The cellular processes associated with the onset and progression of diet-induced metabolic syndrome are insufficiently understood. To identify the mechanisms underlying the pathological changes associated with short and long-term exposure to excess dietary fat, hepatic gene expression of ApoE3Leiden mice fed chow and two types of high-fat (HF) diets was monitored using microarrays during a 16-week period. A functional characterization of 1663 HF-responsive genes reveals perturbations in lipid, cholesterol and oxidative metabolism, immune and inflammatory responses and stress-related pathways. The major changes in gene expression take place during the early (day 3) and late (week 12) phases of HF feeding. This is also associated with characteristic opposite regulation of many HF-affected pathways between these two phases. The most prominent switch occurs in the expression of inflammatory/immune pathways (early activation, late repression) and lipogenic/adipogenic pathways (early repression, late activation). Transcriptional network analysis identifies NF-kappaB, NEMO, Akt, PPARgamma and SREBP1 as the key controllers of these processes and suggests that direct regulatory interactions between these factors may govern the transition from early (stressed, inflammatory) to late (pathological, steatotic) hepatic adaptation to HF feeding. This transition observed by hepatic gene expression analysis is confirmed by expression of inflammatory proteins in plasma and the late increase in hepatic triglyceride content. In addition, the genes most predictive of fat accumulation in liver during 16-week high-fat feeding period are uncovered by regression analysis of hepatic gene expression and triglyceride levels. The transition from an inflammatory to a steatotic transcriptional program, possibly driven by the reciprocal activation of NF-kappaB and PPARgamma regulators, emerges as the principal signature of the hepatic adaptation to excess dietary fat. These findings may be of essential interest for devising new strategies aiming to prevent the progression of high-fat diet induced pathologies.
    PLoS ONE 02/2009; 4(8):e6646. · 4.09 Impact Factor
  • Source
    Article: Rarity of TLR4 Asp299Gly and Thr399Ile polymorphisms in the Korean population.
    Yeun Sun Kim, You Jin Hwang, Sung Yong Kim, Sun Mee Yang, Ki Young Lee, Ie Byung Park
    [show abstract] [hide abstract]
    ABSTRACT: Activation of the innate immune system and chronic low-grade inflammation are thought to be involved in the pathogenesis of atherosclerosis and also thought to be associated with type 2 diabetes and its complications. As a receptor for bacterial lipopolysaccharide and heat-shock proteins, Toll-like receptor 4 (TLR4) is one of the central regulators of the immune response. Recent studies have reported an association between TLR4 polymorphisms and diabetes and its complications in Caucasian populations. In this study, we analyzed the association between TLR4 gene polymorphisms in patients with features of type 2 diabetes and healthy controls in Korea. Two polymorphisms of the TLR4 gene (Asp299Gly and Thr399Ile) were examined in 225 diabetic patients and 153 healthy controls using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and single-strand conformation polymorphism (SSCP). No Asp299Gly or Thr399Ile mutations were detected in any of the 378 subjects. Seven subjects from each group who had slightly different SSCP patterns were selected for sequencing, but we found no TLR4 polymorphisms on Exon3. The Asp299Gly and Thr399Ile TLR4 gene polymorphisms were absent in both groups, which was similar to the results for Japanese and Chinese Han subjects. Our data and other Asian data suggest that a racial difference can be found in the frequency of the TLR4 polymorphism.
    Yonsei Medical Journal 03/2008; 49(1):58-62. · 1.14 Impact Factor
  • Source
    Article: Role of Toll-like receptor 4/NF-kappaB pathway in monocyte-endothelial adhesion induced by low shear stress and ox-LDL.
    Qing-Wu Yang, Lin Mou, Feng-Lin Lv, Jing-Zhou Wang, Lin Wang, Hong-Jie Zhou, Dong Gao
    [show abstract] [hide abstract]
    ABSTRACT: TLR4 plays an important role in atherosclerosis, but little is known about the precise mechanism. Herein, we investigated the role of TLR4/NF-kappaB signaling pathway in monocyte-endothelial adhesion induced by low shear stress and Ox-LDL. We found that low shear stress up-regulated TLR4 expression in endothelial cells, and that ox-LDL exerted an obvious synergistic action as revealed by RT-PCR and Western blotting analysis. Low shear stress also significantly up-regulated IL-8 expression in endothelial cells. Meanwhile, NF-kappaB activity and the adhesion force of monocytes were increased, and there was a synergetic action of ox-LDL. However, following transfection with a functional mutant of TLR4 (C3H/HeJ, TLR4 Dicd) or addition of anti-human TLR4 mAb, IL-8 expression was obviously decreased, NF-kappaB activity in cells remarkably inhibited, and the adhesion force of monocyte significantly reduced. Nevertheless, anti-human TLR2 mAb had no similar effects. These findings suggest that TLR4 may be involved in the early stages of atherosclerosis, associating ox-LDL, inflammation/infection, and low shear stress. Therefore, TLR4 is expected to be a new target for preventing and treating atherosclerosis.
    Biorheology 02/2005; 42(3):225-36. · 1.93 Impact Factor
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.

Keywords

arterial circumference
 
Carotid artery ligation
 
contralateral artery
 
endogenous Tlr4 ligands
 
exogenous lipopolysaccharides
 
extra domain
 
genetic evidence
 
heat shock protein 60
 
Hsp60 mRNA levels
 
matrix turnover
 
neointima formation
 
outward arterial
 
plaque formation
 
subsequent outward arterial
 
Tlr4 activation
 
Tlr4 expression
 
Tlr4 ligands
 
Tlr4-deficient mice
 
Toll-like receptor 4
 
vulnerable plaque phenotype