Toll-Like Receptor 4 Is Involved in Outward Arterial Remodeling

Leiden University, Leyden, South Holland, Netherlands
Circulation (Impact Factor: 14.43). 02/2004; 109(3):393-8. DOI: 10.1161/01.CIR.0000109140.51366.72
Source: PubMed


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.

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    • "), 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. "
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    • "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). "
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    • "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. "
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