| 1. |
- Bengtsson, Eva, et al.
(author)
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Lack of the Cysteine-Protease Inhibitor Cystatin C Promotes Atherosclerosis in Apolipoprotein E-Deficient Mice.
- 2005
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In: Arteriosclerosis, Thrombosis and Vascular Biology. - 1524-4636. ; 25:10, s. 2151-2156
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Journal article (peer-reviewed)abstract
- Objective - Degradation of extracellular matrix plays an important role in growth and destabilization of atherosclerotic plaques. Cystatin C, inhibitor of the collagen- and elastin-degrading cysteine proteases of the cathepsin family, is produced by virtually all cell types. It is present in the normal artery wall but severely reduced in human atherosclerotic lesions. Methods and Results - To determine the functional role of cystatin C in atherosclerosis, we crossed cystatin C - deficient ( cysC(-/-)) mice with apolipoprotein E - deficient ( apoE(-/-)) mice. After 25 weeks of atherogenic diet, mice lacking apoE and cystatin C (cysC(-/-) apoE(-/-)) had larger subvalvular plaques compared with cysC(+/+) apoE(-/-) mice (766 000 +/- 20 000 mu m(2) per section versus 662 000 +/- 19 000 mu m(2) per section; P = 0.001), suggesting an atheroprotective role of cystatin C. The plaques from cysC(-/-) apoE(-/-) mice were characterized by increased total macrophage content. To determine which cellular source is important for the antiatherosclerotic effect of cystatin C, we performed bone marrow transplantations. ApoE(-/-) mice were transplanted with either cysC(-/-) apoE(+/+) or cysC(+/+) apoE(-/-) bone marrow. No significant differences in plaque area, macrophage, collagen, or lipid content of subvalvular lesions between the 2 groups were detected. Conclusions - The result suggests that the protective role of cystatin C in atherosclerosis is dependent primarily on its expression in nonhematopoietic cell types.
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| 2. |
- Brånén, Lena, et al.
(author)
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Inhibition of Tumor Necrosis Factor-{alpha} Reduces Atherosclerosis in Apolipoprotein E Knockout Mice.
- 2004
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In: Arteriosclerosis, Thrombosis and Vascular Biology. - 1524-4636. ; 24:11, s. 2137-2142
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Journal article (peer-reviewed)abstract
- Objective - Inflammation plays an important role in atherosclerosis. One of the most potent pro-inflammatory cytokines is tumor necrosis factor-alpha (TNF-alpha), a cytokine identified to have a pathogenic role in chronic inflammatory diseases such as rheumatoid arthritis ( RA). The aim of the study was to evaluate the importance of TNF-alpha in atherogenesis. Methods and Results - Mice deficient in both apolipoprotein E (apoE) and TNF-alpha were compared regarding their atherosclerotic burden. Mice were fed a Western-style diet (WD) or normal chow. Mice deficient in both apoE and TNF-alpha exhibited a 50% ( P = 0.035) reduction of relative lesion size after 10 weeks of WD. Bone marrow transplantation of apoEo mice with apoE(o)tnf-alpha(o) bone marrow resulted in a 83% ( P = 0.021) reduction after 25 weeks on WD. In apoE knockout mice treated with recombinant soluble TNF receptor I releasing pellets, there was a reduction in relative lesion size after 25 weeks of 75% ( P = 0.018). Conclusions - These findings demonstrate that TNF-alpha is actively involved in the progression of atherosclerosis. Accordingly, TNF-alpha represents a possible target for prevention of atherosclerosis. This may be of particular importance in rheumatoid arthritis because these patients have an increased risk for cardiovascular disease.
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| 3. |
- Brånén, Lena
(author)
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Tumor Necrosis Factor-alpha as a target cytokine in vascular disease
- 2004
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Doctoral thesis (other academic/artistic)abstract
- Inflammation plays an important role in atherosclerosis. One of the most potent pro-inflammatory cytokines is tumor necrosis factor-alpha (TNF-a), a cytokine identified to have a pathogenic role in chronic inflammatory diseases such as rheumatoid arthritis (RA). The major objectives of this investigation was to establish a role for TNF-a in the development of atherosclerosis and neointimal formation. The two pathological conditions have many things in common. Both are hyperplastic events with vesselwall remodeling and an element of inflammation: accumulation of leukocytes and macrophages in a remoding lipid-laden vessel wall. Intimal hyperplasia is a process present both in early atherosclerosis and after vascular intervention such as balloon angioplasty. The processes are inextricably entwined since restenosis is the consequence of interventions done in attempts to sway atherosclerotic disease. We report that atherosclerosis is inhibited in mice when TNF-a is depleted by genetic manipulation, by circulating antagonizers or when it is targeted in hematopoietic cells. This attenuation is caused by TNF-a derived from hematopoietic cells and is independent of circulating lipid levels. We also report that neointimal formation is inhibited by genetic deletion of TNF-a. The reduction is accompanied with less matrix deposition and smaller cell populations in the TNF-a depleted animals. We also report that smooth muscle cells isolated from the neointima of injured rat aortas are characterized by increased expression of TNF-a in response to interleukin-1b and interferon-g compared to medial smooth muscle cells. Cytokine-induced apoptosis in intimal cells was effectively inhibited by treatment with antibodies against TNF-receptors. These findings demonstrate that TNF-a might be actively involved in the progression of atherosclerosis and neointimal hyperplasia. These findings also sugggest that endogenous activation of TNF receptors may represent a way to limit accumulation of smooth muscle cells in injured arteries. This mechanism may also be important in SMC death in advanced atherosclerotic plaques.
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| 4. |
- Zaina, Silvio, et al.
(author)
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Insulin-like growth factor II plays a central role in atherosclerosis in a mouse model.
- 2002
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In: Journal of Biological Chemistry. - 1083-351X .- 0021-9258. ; 277:6, s. 4505-4511
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Journal article (peer-reviewed)abstract
- Insulin-like growth factor II is a fetal promoter of cell proliferation that is involved in some forms of cancer and overgrowth syndromes in humans. Here, we provide two sources of genetic evidence for a novel, pivotal role of locally produced insulin-like growth factor II in the development of atherosclerosis. First, we show that homozygosity for a disrupted insulin-like growth factor II allele in mice lacking apolipoprotein E, a widely used animal model of atherosclerosis, results in aortic lesions that are approximately 80% smaller and contain approximately 50% less proliferating cells compared with mice lacking only apolipoprotein E. Second, targeted expression of an insulin-like growth factor II transgene in smooth muscle cells, but not the mere elevation of circulating levels of the peptide, causes per se aortic focal intimal thickenings. The insulin-like growth factor II transgenics presented here are the first viable mutant mice spontaneously developing intimal masses. These observations provide the first direct evidence for an atherogenic activity of insulin-like growth factor II in vivo.
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