| Study BackgroundCoronary artery disease (CAD) and other cardiovascular diseases were serious harmful to human health, and atherosclerosis (AS) was the main pathologic basis. A large number of epidemiological and clinical studies have shown that high-density lipoprotein cholesterol (HDL-C) levels was related to CAD incidence and mortality inversely and was an independent factor for anti-AS and CAD. Currently it is considered that the great role of high-density lipoprotein (HDL) played in cardiovascular protection extent was due to the function of reverse cholesterol transport (RCT) which was mediated by HDL receptor as ATP-binding cassette transporter A1 (ATP-binding cassette transporter 1, ABCA1) and scavenger receptor Class B typeâ… (SR-BI). RCT was the only way to discharge excess cholesterol and considered as one of the main mechanisms anti-atherosclerosis at present.Low level of HDL-C was an independent risk factor for CAD. The traditional research showed that HDL-C level and CAD incidence and mortality rates were negatively correlated, but recent studies showed that the level of HDL-C could not accurately represent the whole function of HDL. The anti-AS function of HDL was mainly manifested in RCT, anti-inflammatory and anti-oxidation. HDL is composed of different size, density, composition and function of the heterogeneity of lipoprotein particle composition. Application technology, density gradient ultracentrifugation, HDL particles are classified to, according to their density, HDL1, HDL2, and HDL3 three kinds of sub-classes. HDL is HDL2 and HDL3-based (each 1/3 and 2/3), while the HDL1 little content. HDL3 is small, density, immature particles, while HDL2 as large, less dense, mature particles. These HDL subclasses played different roles in the promotion of RCT and anti-oxidant function.Recent studies found that rosiglitazone have been added value as a peroxisome proliferator-activated receptor y(PPARy) agonists. Both in the diabetic state or in non-diabetic state, rosiglitazone can inhibit the progress of AS, which one important way is to increase the cellular expression of ABCA1. Increased ABCA1 expression significantly elevated plasma HDL-C levels, while inhibiting the progress of AS. However, the effects of rosiglitazone on SR-BI and RCT in vivo have not been reported at home and abroad.Therefore, in this study, we studied by the model of AS rabbits, using chemical precipitation measured HDL subfraction (HDL2 and HDL3) concentration;using flow cytometry of rosiglitazone on hepatic cells, macrophages ABCA1 and SR-BI protein expression; using liquid scintillation counting to detect peritoneal macrophages and liver cells to [3H] cholesterol. By using those methods, we indirectly reflect the roll-out rate of RCT level. The aorta routine HE staining for histological observation, was used for measurement of the aortic intima-media thickness (IMT). From the study, we explored the new mechanisms of rosiglitazone on HDL function in AS rabbitts mode.ObjectivesWe studied the effects of ABCA1, SR-BI protein expressions in hepatic cells, peritoneal macrophages, the proportion of HDL subclasss (HDL2/HDL) during the atherosclerogenesis. At the same time, we analysis effects of PPARy agonist rosiglitazone on those index, and explored the new mechanism rosiglitazone of anti-atherosclerosis.Methods18 New Zealand white rabbits were randomly divided into three groups:â‘ Control group:normal diet feeding;â‘¡AS group:fed a high cholesterol diet;â‘¢rosiglitazone groups:high cholesterol diet and rosiglitazone 0.5mg/kg/d. After 12 weeks of feeding, serum lipid was measured by enzymatic determination, expression levels of ABCA1/SB-BI of hepatotic cells, peritoneal macrophages by flow cytometry, cholesterol efflux rate by liquid scintillation counting, HDL subclass by chemical precipitation, and the aorta IMT by histological characteristics at the end of 12 weeks after the confirmation of the death of the rabbits.Results1) There were no significant differences in the plasma TC, TG, LDL-C, HDL-C, VLDL-C, NHDL-C and body weight among the four groups at the baseline. After 12 weeks of experiment, serum in control group was brighter, AS group and the rosiglitazone group were milky white in appearance. Compared with control group, plasma TC, LDL-C, TG, HDL-C, VLDL-C levels in AS group were significantly increased. Compared with the AS group, plasma HDL-C levels in rosiglitazone group were significantly increased, and NHDL-C significantly reduced.2) Compared with control group, ABCA1 and SR-BI expressions in peritoneal macrophage and hepatic cells in AS group were significantly reduced. The expression of ABCA1 and SR-BI in peritoneal macrophage and hepatic cells in rosiglitazone group were increased significantly compared with AS group.3) Compared with the normal control group, AS group of peritoneal macrophages, liver cells, [3H] cholesterol transfer out rate was lower rosiglitazone group peritoneal macrophages, liver cells; [3H] cholesterol transfer out rate with the control group, no significant difference. The rosiglitazone group peritoneal macrophages, liver cells, [5H] cholesterol transferred out rate in the AS increased significantly.4) Rabbits in each group of serum HDL subfractions structure changed, with the normal control group, AS group significantly decreased the proportion of HDL2/HDL; with the AS group, rosiglitazone group HDL2/HDL ratio increased significantly.5) compared with AS group, probucol reduced aortic IMT and plaque area significantly (P< 0.001)Conclusions1. The plasma HDL-C levels were significantly elevated and NHDL-C decreased after the intervention by rosiglitazone in AS rabbitts.2. Rosiglitazone promotes RCT by up-regulating ABCA1 and SR-BI expressions in macrophages and hepatocytes.3. In the AS state, HDL subfraction ratio (HDL2/HDL) reduced; while rosiglitazone raised HDL2/HDL proportion and promoted HDL mature and improved HDL function.4. Rosiglitazone significantly reduced aortic intima-media thickness of AS rabitts and played a positive role on anti-AS process. |
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