056). AZ876 (20 ��mol?kg?1) markedly reduced atherosclerosis development with regard to lesion number (?59%), lesion area (?91%) and the abundance of severe inhibitor lesions (17 �� 23%, all P < 0.001). GW3965 was more potent in inhibiting atherosclerosis than the low dose of AZ876, resulting in reductions in the number of lesions (by 38%, P < 0.05) and lesion area (by 74%, P < 0.001) and less severe lesions (28 �� 21%, P < 0.01) as compared with control. We observed no effect of 5 ��mol?kg?1 AZ876 on the amount of undiseased segments (14 �� 21% in the control). However, 20 ��mol?kg?1?day?1 AZ876 and GW3965 clearly increased the amount of undiseased segments (to 58 �� 23%, P < 0.001 and 44 �� 28%, P < 0.01, respectively). Both high-dose AZ876 and GW3965 were significantly (P < 0.001 and P < 0.

05, respectively) more potent in preventing lesion development than the low-dose AZ876 treatment. Figure 4 APOE*3Leiden mice were treated for 20 weeks with a Western-type diet alone (control) or supplemented with AZ876 (5 or 20 ��mol?kg?1?day?1) or GW3965 (17 ��mol?kg?1?day?1). The … We then assessed the lesion composition by measuring the collagen and the SMC content of the lesions, both considered to stabilize the lesions, and the amount of macrophages, known to be a destabilizing component in the lesions (Delsing et al., 2001; Libby, 2002). As shown in Figure 5, treatment with AZ876 in either dose did not affect the collagen or SMC content, relative to values in the control lesions. GW3965, however, reduced the collagen content by 23% (P < 0.

01) as compared with control, resulting in significantly less collagen content than in the 20 ��mol?kg?1?day?1 AZ876 group, without affecting the SMC content. Treatment with either dose of AZ876 or GW3965 did not significantly affect the macrophage content (Figure 5). In summary, GW3965 induced a less stable lesion phenotype as compared with the control, whereas AZ876 in either dose did not affect the lesion composition. Figure 5 The effect of 5 or 20 ��mol?kg?1?day?1 AZ876 or GW3965 (17 ��mol?kg?1?day?1) on lesion composition was assessed by measuring the macrophage, collagen and smooth muscle cell … As a functional parameter for vessel wall inflammation, we also investigated the numbers of monocytes adhering to the activated endothelium of the aortic root, which is considered the first step in lesion development.

A representative image of adhering monocytes is presented in Figure 6A. The summary data (Figure 6B) show that the AV-951 number of adherent macrophages was reduced by 72% upon treatment with 20 ��mol?kg?1?day?1 AZ876 and by 53% in the GW3965-treated mice. These anti-inflammatory effects of both LXR agonists were confirmed by plasma analysis of inflammatory cytokines TNF-��, IL-1�� and IL-6 (Table 4), which were decreased upon treatment with 20 ��mol?kg?1 AZ876 and with GW3965.