The Protective Effect of Bosentan against Atherosclerosis in Apolipoprotein E-Deficient Mice Is Mediated by miRNA-21.

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 (R)), 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.