Abstract
Vascular calcification is an independent risk factor for plaque instability and is associated with endothelial cell function. Here, we investigated the role of endothelial cell function in the calcification of atherosclerotic plaques. We hypothesized that atherosclerosis would be associated with endothelial dysfunction and that bosentan (Tracleer®), a dual endothelin-receptor antagonist, would preserve endothelial cell function in an apolipoprotein E-deficient (ApoE−/−) mouse model of atherosclerosis. Accordingly, 4–6-week-old ApoE−/− mice were fed a high-fat diet and treated with bosentan, and the effects of this treatment on body weight and blood lipid concentrations was evaluated. Endothelial damage in the aortic arch was assessed immunohistochemically to detect the proapoptotic proteins PDCD4, caspase-3, and Bax and the antiapoptotic protein Bcl-2. Notably, bosentan treatment was associated with decreased concentrations of these proteins and of blood lipids in ApoE−/− mice. Consistent with these findings, we observed increased concentrations of miRNA-21 and PDCD4 mRNA expression in the aortic arch endothelium after bosentan treatment. We conclude that bosentan can prevent endothelial cell death and protect against atherosclerosis in ApoE-deficient mice by upregulating miRNA-21.
Highlights
® sclerosis would be associated with endothelial dysfunction and that bosentan (Tracleer ), a dual endothelin-receptor antagonist, would preserve endothelial cell function in an apolipoprotein E-deficient (ApoE− /− ) mouse model of atherosclerosis
At week 12, mice from the control group and ApoE− /− groups were sacrificed, and the aortic sinus tissues were collected. e successful inclusion of atherosclerosis was shown in the ApoE− /− group. e ApoE− /− mice presented with features of typical atherosclerosis, such as a thin fibrous cap and the presence of foam cells and cholesterol crystals within the atherosclerotic plaque (Figure 1)
Consistent with the immunohistochemistry data, we observed a significant increase in the expression of Programmed cell death 4 (PDCD4) mRNA in the ApoE− /− group relative to the control group, whereas bosentan treatment induced a dramatic decrease in PDCD4 expression (Figure 8)
Summary
® sclerosis would be associated with endothelial dysfunction and that bosentan (Tracleer ), a dual endothelin-receptor antagonist, would preserve endothelial cell function in an apolipoprotein E-deficient (ApoE− /− ) mouse model of atherosclerosis. Bosentan treatment was associated with decreased concentrations of these proteins and of blood lipids in ApoE− /− mice. Consistent with these findings, we observed increased concentrations of miRNA-21 and PDCD4 mRNA expression in the aortic arch endothelium after bosentan treatment. This protein acts as a tumor suppressor [21] and is upregulated during apoptosis It remains unclear how miRNA-21 [22] regulates the specific and potentially pathological activities of PDCD4, such as proliferation and apoptosis. In this study, BioMed Research International we generated an animal model of atherosclerosis by raising apolipoprotein E-deficient (ApoE− /− ) mice on a high-fat diet and investigated the expression of miRNA-21 and its target PDCD4 during the progression of atherosclerosis in these animals
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