Rosiglitazone attenuates atherosclerosis and increases high-density lipoprotein function in atherosclerotic rabbits

Abstract

Rosiglitazone has been found to have anti-atherogenic effects and to increase serum high-density lipoprotein (HDL) cholesterol (HDL-C) levels. However, in vivo studies investigating the regulation of adenosine triphosphate-binding cassette transporter A1 (ABCA1) and scavenger receptor class B type I (SR-BI) by rosiglitazone are limited. Moreover, the effects of rosiglitazone on the function and levels of HDL are unclear. In the present study, we investigated the effects of rosiglitazone on HDL function and its mechanisms of action in atherosclerotic rabbits. Our results revealed that rosiglitazone induced a significant increase in serum HDL-C levels, paraoxonase 1 (PON1) activity, [(3)H]cholesterol efflux rates, and the expression of ABCA1 and SR-BI in hepatocytes and peritoneal macrophages. The expression of ABCA1 was also increased in aortic lesions. Rosiglitazone markedly reduced serum myeloperoxidase (MPO) activity, aortic intima-media thickness (IMT) and the percentage of plaque area in the aorta. It can thus be concluded that in atherosclerotic rabbits, rosigitazone increases the levels of HDL-C and hinders atherosclerosis. Thus, it improves HDL quality and function, as well as the HDL-induced cholesterol efflux, exerting anti-inflammatory and antioxidant effects.

Figure 1

Representative micrographs of the intimal lesions. H&E staining was performed on aortic sections from rabbits in either (A) control group, (B) AS group and (C) rosiglitazone group. H&E, hematoxylin and eosin; AS, atherosclerosis.

Figure 2

Comparison of HDL-induced cholesterol efflux rates from hepatocytes and peritoneal macrophages among the 3 groups. Data are presented as the means ± SEM, (n=6 in each group). ^*P<0.01, vs. control group; ^**P<0.01, ^***P<0. 05, vs. AS group (ANOVA). HDL, high-density lipoprotein; AS, atherosclerosis.

Figure 3

(A) ABCA1 protein expression in hepatocytes and peritoneal macrophages determined by flow cytometry. (B) SR-B1 protein expression in hepatocytes and peritoneal macrophages determined by flow cytometry. Data are presented as the means ± SEM, (n=6 in each group). ^#P<0.05, ^*P<0.01, ^##P<0.001, vs. control group; ^**P<0.01, ^***P<0. 05, ^****P<0. 001, vs. AS group (ANOVA). ABCA1, adenosine triphosphate binding cassette transporter A1; SR-B1, scavenger receptor class B type I; AS, atherosclerosis.

Figure 4

(A) Hepatocyte ABCA1 mRNA expression quantified by RT-qPCR. (B) Hepatocyte SR-B1 mRNA expression quantified by RT-qPCR. Data are presented as the means ± SEM, (n=6 in each group). ^*P<0.01 vs. control group; ^**P<0.01 vs. AS group (ANOVA). ABCA1, adenosine triphosphate binding cassette transporter A1; SR-B1, scavenger receptor class B type I; AS, atherosclerosis.

Figure 5

Aortic sections were subjected to immunohistochemical staining for ABCA1 protein localization. Representative images captured at magnification, ×40, ×100 and ×200. ABCA1, adenosine triphosphate binding cassette transporter A1; AS, atherosclerosis.

Figure 6

Aortic sections were subjected to immunohistochemical staining for SR-B1 protein localization. Representative images captured at magnification ×40, ×100 and ×200. SR-B1, scavenger receptor class B type I; AS, atherosclerosis.

Figure 7

Treatment with rosiglitazone increased PON1 activity (U/ml) and reduced MPO activity (U/l) in the rosiglitazone group, compared with the AS group. (A) Serum PON1 activity. (B) Serum MPO activity. Data are presented as mean ± SEM, (n=6 in each group). ANOVA, P<0.05; ^*P<0.01 vs. control group; ^**P<0.05 vs. AS group. PON1, paraoxonase 1; MPO, myeloperoxidase; AS, atherosclerosis.