Article

Toll-Like Receptor 4 Is Involved in Outward Arterial Remodeling

Leiden University, Leyden, South Holland, Netherlands
Circulation (Impact Factor: 14.95). 02/2004; 109(3):393-8. DOI: 10.1161/01.CIR.0000109140.51366.72
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.

Download full-text

Full-text

Available from: Aryan Vink, Aug 29, 2015
0 Followers
 · 
126 Views
  • Source
    • "), its role in advanced and unstable atherosclerotic plaques has yet to be fully assessed, and few studies point to an association between TLR4 activation and plaque rupture (Methe et al., 2005; Geng et al., 2006; Ishikawa et al., 2008). TLR4 has been shown to be important in the process of expansive arterial remodeling and in matrix breakdown; the latter process involves cell migration and leads to higher expression levels of matrix metalloproteinases (MMPs), mainly MMP-2 and MMP-9, which are involved in extracellular matrix (ECM) degradation (Hollestelle et al., 2004). Alongside the classic endogenous ligands, the endogenously produced TLR ligands most relevant to the context of atherosclerosis are the minimally modified low-density lipoproteins (mmLDLs) and the oxidized LDLs (oxLDLs), together with their active components; these include oxidized phospholipids, cholesterol oxidation products (oxysterols), and free and esterified aldehydes. "
    [Show abstract] [Hide abstract]
    ABSTRACT: It is now thought that atherosclerosis, although due to increased plasma lipids, is mainly the consequence of a complicated inflammatory process, with immune responses at the different stages of plaque development. Increasing evidence points to a significant role of Toll-like receptor 4 (TLR4), a key player in innate immunity, in the pathogenesis of atherosclerosis. This study aimed to determine the effects on TLR4 activation of two reactive oxidized lipids carried by oxidized low-density lipoproteins, the oxysterol 27-hydroxycholesterol (27-OH) and the aldehyde 4-hydroxynonenal (HNE), both of which accumulate in atherosclerotic plaques and play a key role in the pathogenesis of atherosclerosis. Secondarily, it examined their potential involvement in mediating inflammation and extracellular matrix degradation, the hallmarks of high-risk atherosclerotic unstable plaques. In human promonocytic U937 cells, both 27-OH and HNE were found to enhance cell release of IL-8, IL-1β, and TNF-α and to upregulate matrix metalloproteinase-9 (MMP-9) via TLR4/NF-κB-dependent pathway; these actions may sustain the inflammatory response and matrix degradation that lead to atherosclerotic plaque instability and to their rupture. Using specific antibodies, it was also demonstrated that these inflammatory cytokines increase MMP-9 upregulation, thus enhancing the release of this matrix-degrading enzyme by macrophage cells and contributing to plaque instability. These innovative results suggest that, by accumulating in atherosclerotic plaques, the two oxidized lipids may contribute to plaque instability and rupture. They appear to do so by sustaining the release of inflammatory molecules and MMP-9 by inflammatory and immune cells, for example, macrophages, through activation of TLR4 and its NF-κB downstream signaling. © 2015 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.
    Aging cell 03/2015; 14(4). DOI:10.1111/acel.12322 · 5.94 Impact Factor
  • Source
    • "Next, we used bone marrow-derived macrophages (BMMs) isolated from WT and CaMKIIδ−/− mice to confirm the presence and inducibility of CaMKII. Since toll-like receptor 4 (TLR4) activation contributes to arteriogenesis [34], [35], we assessed BMM CaMKIIγ and CaMKIIδ mRNA expression following exposure to lipopolysaccharide (LPS), a known TLR4 agonist. Low levels of both CaMKIIγ and CaMKIIδ were detected in WT BMMs at baseline, and exposure to LPS promoted a 5-fold increase in CaMKIIδ mRNA levels (Figure 4B, left panel). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Sustained hemodynamic stress mediated by high blood flow promotes arteriogenesis, the outward remodeling of existing arteries. Here, we examined whether Ca(2+)/calmodulin-dependent kinase II (CaMKII) regulates arteriogenesis. Ligation of the left common carotid led to an increase in vessel diameter and perimeter of internal and external elastic lamina in the contralateral, right common carotid. Deletion of CaMKIIδ (CaMKIIδ-/-) abolished this outward remodeling. Carotid ligation increased CaMKII expression and was associated with oxidative activation of CaMKII in the adventitia and endothelium. Remodeling was abrogated in a knock-in model in which oxidative activation of CaMKII is abolished. Early after ligation, matrix metalloproteinase 9 (MMP9) was robustly expressed in the adventitia of right carotid arteries of WT but not CaMKIIδ-/- mice. MMP9 mainly colocalized with adventitial macrophages. In contrast, we did not observe an effect of CaMKIIδ deficiency on other proposed mediators of arteriogenesis such as expression of adhesion molecules or smooth muscle proliferation. Transplantation of WT bone marrow into CaMKIIδ-/- mice normalized flow-mediated remodeling. CaMKIIδ is activated by oxidation under high blood flow conditions and is required for flow-mediated remodeling through a mechanism that includes increased MMP9 expression in bone marrow-derived cells invading the arterial wall.
    PLoS ONE 08/2013; 8(8):e71550. DOI:10.1371/journal.pone.0071550 · 3.23 Impact Factor
  • Source
    • "p = 0.0037) (figure3B). Previously, we showed that TLR4 induced neointima formation via local LPS application caused outward remodeling [4], [18]. Therefore, we compared the total vessel wall areas of both groups to study the outward remodeling response. "
    [Show abstract] [Hide abstract]
    ABSTRACT: RP105 (CD180) is TLR4 homologue lacking the intracellular TLR4 signaling domain and acts a TLR accessory molecule and physiological inhibitor of TLR4-signaling. The role of RP105 in vascular remodeling, in particular post-interventional remodeling is unknown. TLR4 and RP105 are expressed on vascular smooth muscle cells (VSMC) as well as in the media of murine femoral artery segments as detected by qPCR and immunohistochemistry. Furthermore, the response to the TLR4 ligand LPS was stronger in VSMC from RP105(-/-) mice resulting in a higher proliferation rate. In RP105(-/-) mice femoral artery cuff placement resulted in an increase in neointima formation as compared to WT mice (4982±974 µm(2) vs.1947±278 µm(2),p = 0.0014). Local LPS application augmented neointima formation in both groups, but in RP105(-/-) mice this effect was more pronounced (10316±1243 µm(2) vs.4208±555 µm(2),p = 0.0002), suggesting a functional role for RP105. For additional functional studies, the extracellular domain of murine RP105 was expressed with or without its adaptor protein MD1 and purified. SEC-MALSanalysis showed a functional 2∶2 homodimer formation of the RP105-MD1 complex. This protein complex was able to block the TLR4 response in whole blood ex-vivo. In vivo gene transfer of plasmid vectors encoding the extracellular part of RP105 and its adaptor protein MD1 were performed to initiate a stable endogenous soluble protein production. Expression of soluble RP105-MD1 resulted in a significant reduction in neointima formation in hypercholesterolemic mice (2500±573 vs.6581±1894 µm(2),p<0.05), whereas expression of the single factors RP105 or MD1 had no effect. RP105 is a potent inhibitor of post-interventional neointima formation.
    PLoS ONE 07/2013; 8(7):e67923. DOI:10.1371/journal.pone.0067923 · 3.23 Impact Factor
Show more