Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
, 215 (2), 348-54

TRAIL Attenuates the Development of Atherosclerosis in Apolipoprotein E Deficient Mice

Affiliations

TRAIL Attenuates the Development of Atherosclerosis in Apolipoprotein E Deficient Mice

Victoria Watt et al. Atherosclerosis.

Abstract

TRAIL (tumour necrosis factor-related apoptosis inducing ligand) is most often reported to induce apoptosis in tumour cells. It is expressed in artery walls but its role and regulation in vascular pathologies is little studied. We aimed to measure the effect of genetic deletion of TRAIL on atherosclerosis in a mouse model. TRAIL was mainly expressed in endothelium, smooth muscle cells and macrophages within plaques. The absence of TRAIL in chow and in fat-fed mice led to greater lesion coverage in aortae (8 weeks, % area ± SEM), n=7-8, 1.24 ± 0.2 (no TRAIL, chow diet) vs. 0.42 ± 0.1, p<0.01 and 3.4 ± 0.8 (no TRAIL, Western diet) vs. 0.94 ± 0.2, p<0.01 and larger, smooth muscle cell rich lesions at aortic roots than control mice (8 weeks, mean lesion area/total cross sectional area ± SEM, n=7-8, 0.17 ± 0.01 (no TRAIL, chow diet) vs. 0.135 ± 0.006, p<0.05 and 0.36 ± 0.03 (no TRAIL, Western diet) vs. 0.23 ± 0.02, p<0.05) particularly at early time points. The larger early lesions appeared to be as a result of increased smooth muscle cells in lesions of TRAIL deficient, pro-atherosclerotic animals. We conclude that TRAIL attenuates plaque size at early stages of atherosclerosis.

Figures

Fig. 1
Fig. 1
TRAIL expression in an atheromatous aortic sinus lesion (8 weeks). (A) TRAIL protein in medial and peri-adventitial cells (arrows denote VSMC). (B) High power of (A) to show individual cell associated expression. (C) Macrophage staining (F480 antigen) in the same lesion as (A) and (B) to show macrophage expression (arrows denote one TRAIL positive and one TRAIL negative macrophage). (D) Negative control (isotype).
Fig. 2
Fig. 2
The effect of TRAIL on atheroma development in ApoE−/− mice fed chow or a Western diet. Analysis of atheromatous lesions in en face aortae preparations using Oil red O staining from TRAIL−/−ApoE−/− and ApoE−/− mice fed chow or Western diet for 8 weeks (A) or 12 weeks (B) showed that the absence of TRAIL leads to an increase in % lesion area (expressed as a percentage of total surface area of the aorta). For (A), *p < 0.01 vs. ApoE−/− fed chow and Western, respectively, at 8 weeks, n = 8, Mann–Whitney U Test. For (B), significance only seen on a chow diet after 12 weeks of feeding, *p < 0.001 vs. ApoE−/− chow, n = 9–14, Mann–Whitney U Test.
Fig. 3
Fig. 3
The effect of TRAIL on lesional area at the aortic sinus. ApoE−/− or TRAIL−/−ApoE−/− mice were fed chow or Western diet for 8 weeks (A) or 12 weeks, n = 9–14 (B) and lesion area assessed by Alcian Blue/Elastic Van Gieson staining. ApoE−/− mice on both diets had smaller lesions than TRAIL−/−ApoE−/− mice but only at the 8 week timepoint. *p < 0.05, Mann–Whitney U test.
Fig. 4
Fig. 4
Representative images of atheromatous lesions in ApoE−/− and TRAIL−/−ApoE−/− mice. En face aorta preparations from ApoE−/− mice (A) and TRAIL−/−ApoE−/− mice (B) fed chow for 12 weeks. Note larger lesions at all sites for the TRAIL−/−ApoE−/− mice compared to ApoE−/− mice. Scale bar represents 2 mm. Aortic sinus lesions in ApoE−/− (C) and TRAIL−/−ApoE−/− mice (D) fed Western diet for 8 weeks. Note larger lesions for the TRAIL−/−ApoE−/− mice compared to ApoE−/− mice. Scale bar represents 200 μm.
Fig. 5
Fig. 5
The effect of TRAIL on atheroma lesion VSMC composition in ApoE−/− mice fed a high fat diet. VSMC indices in aortic sinus lesions from ApoE−/− and TRAIL−/−ApoE−/− mice fed the Western or Paigen diet for 8 weeks. These data show that deletion of TRAIL in ApoE−/− mice fed the Western diet for 8 weeks leads to greater positive staining for α-smooth muscle actin in the lesion (A) compared to mice with functional TRAIL. The data in (B) are from lesions harvested after 12 weeks of feeding. Positive staining in the lesion is expressed as a ratio to total lesion area, data are presented as mean ± SEM, analysis by the Mann–Whitney U test, significant results denoted by *p < 0.05.
Fig. 6
Fig. 6
The effect of TRAIL on macrophages in atheromatous lesions. Quantitation of Mac 3 immunohistochemistry of aortic sinus from ApoE−/− and TRAIL−/−ApoE−/− mice fed chow or Western or diet for 8 (A) or 12 (B) weeks. Macrophage staining after 8 weeks on a chow diet was too low to quantify accurately. There was no significant difference in Mac 3 staining between mouse genotypes or with diet. Area of positive staining for Mac 3 is expressed as a ratio to total lesion area, data are presented as mean ± SEM, analysis by the Mann–Whitney U test, significant results denoted by *p < 0.05.

Similar articles

See all similar articles

Cited by 17 articles

See all "Cited by" articles

References

    1. Pan G. O.R.K., Chinnaiyan A.M., Gentz R. The receptor for the cytotoxic ligand TRAIL. Science. 1997;276:111–113. - PubMed
    1. Degli-Eposti M.A., Smolak P.J., Walczak H. Cloning and characterization of TRAIL-R3, a novel member of the emerging TRAIL receptor family. J Exp Med. 1997;186:1165–1170. - PMC - PubMed
    1. Emery J.G., McDonnell P., Burke M.B. Osteoprotegerin is a receptor for the cytotoxic ligand TRAIL. J Biol Chem. 1998;273(23):14363–14367. - PubMed
    1. Daniels R.A., Turley H., Kimberley F.C. Expression of TRAIL and TRAIL receptors in normal and malignant tissues. Cell Res. 2005;15:430–438. - PubMed
    1. Choi J.W., Song J.S., Pai S.H. Associations of serum TRAIL concentrations, anthropometric variables, and serum lipid parameters in healthy adults. Ann Clin Lab Sci. 2004;34(4):400–404. - PubMed

Publication types

MeSH terms

Substances

Feedback