| Background:Metabolic Syndrome(MS) is characterized as high blood pressure, metabolic disorder of blood glucose and blood lipid, and obese, which has been identified as a risk factor of atherosclerosis(AS). The peroxisome proliferator activated receptor agonist(PPAR-α and PPAR-y) demonstrated the effect of anti-atherosclerosis through improving the metabolic disorder of blood glucose and lipid and the inflammation state in MS patients, which was usually administered alone in clinical practice. We speculate that the combined used of PPAR-a agonists fenofibrate and PPAR-y agonists pioglitazone could be more effective than using them alone in improving the atherosclerosis caused by MS. In order to study the effect and mechanism of combined using of fenofibrate and pioglitazone in protecting AS, we established the MS model on rats. Because of the short model-inducing duration, the low cost and better simulating the pathogenesis of MS patients, fructose overfeeding was chosen to establish the MS rat model.Objectives:To establish MS model of SD rats induced by fructose overfeeding, observe the blood glucose, blood lipid, and the pathological changes of aorta. Methods:60rats were randomly assigned to the control group(CG, n=10) and the the model group (MG, n=50).CG rats were fed10weeks with common rat diet in separated cage and the MG rats were fed with high-fructose diet in the same condition. The bodyweight, blood pressure(BP), FBS,FINS,TC,TG,LDL-C,HDL-C,FFA,ALT,AST,BUN, CR and UA were measured in the two groups, HOMA-IR was also studied as well as morphological change of the aorta.Results:Compared to CG, rats in MG exhibited higher tail arterial BP at the4th week and significantly higher BP at the8th week; higher FBS at the10th week; higher serum FINS levels at the4th week and significantly higher serum FINS levels at the8th week; higher HOMA-IR at the4th week; higher serum TG level at the4th week and significantly higher serum TG level at the8th week; higher serum TC level at the4th week and significantly serum TC level at the10th week; higher serum LDL-C level at the4th week and significantly higher serum LDL-C level at the10th week; higher srum FFA levels at the4week and significantly higher FFA level at the8th week; higher serum HDL-C level at the10th week, higher serum ALT, AST and UA level at the8th week and higher serum BUN and CR level at the10th week. MG Rat’s aortic intima structure was disordered and unevenly thickened, internal elastic membrane was damaged and ruptured in varying degrees, the film was thickened and the elastic fiber structure was disordered, the smooth muscle cells were proliferated and extended to intima, causing thickened tunica intima and medial.Conclusions:1)The MS rat model was successful established by fructose overfeeding. The model presents the typical MS changes with hyperinsulinemia (HINS), IR, hypertriglyceridemia (HTG), hypertension, high serum non-esterified fatty acid, and the impairment of the liver function and renal function.2)There were atherosclerosis in the MS model of rats. Background:The MS rat model was successfully established in first part of our study, which presented hyperinsulinemia, insulin resistance, Hypertriglyceridemia, hypertension, and atherosclerosis as well. We continue to investigate the effect and mechanism of combined using of fenofibrate and pioglitazone in protecting AS in the MS rat model. Monocyte/macrophage plays an important role in the development of atherosclerosis, monocytes chemotaxis protein (MCP-1) as a kind of chemokin, which involves not only in promoting mononuclear cells in the atherosclerotic plaque place, but also in making vascular smooth muscle cell proliferation therefore participating in the pathogenesis of atherosclerosis. NF-κB can regulate MCP-1gene coding and damage the integrity of endothelial structure and function, then participates in the formation of atherosclerotic plaque. Thus, in this part, we will investigate the changes of NF-κB,MCP-1,ED-1to explore the mechanism of PPAR-a and PPAR-yon the protection effect for AS in rat MS model.Objectives:To investigate the effects of combined use of PPAR-a and PPAR-y agonists on the weight, blood pressure, metabolism of glucose and lipid, IR,expression of NF-κB,MCP-1,ED-1,and the arterial morphology in rat model with MS. To explore the mechanisms of combined use of PPAR-a and PPAR-y agonists on AS in rats with MS.Methods:42MS rats were randomly assigned to model control group (M group,n=10), Fenofibrate (F group,n=11), Pioglitazone group (P group,n=10), Fenofibrate+Pioglitazone group (F+P group,n=11).6SD rates were assigned to normal group (N group,n=6)which were fed with standard diet. Rats in F group were taken Fenofibrate30mg/kg.d; rats in P group were taken Pioglitazone3mg/kg.d; rats in F+P group were taken both Fenofibrate30mg/kg.d and Pioglitazone3mg/kg.d. The drugs were delivered by gavage with water once a day for4weeks. Weight, blood pressure (SBP), blood glucose(BG), FINS, blood lipid(BL) and liver and kidney function were measureed before and after the intervention in rats. The rats were executed4weeks after, the morphological change and the expression of NF-κB,MCP-1,ED-1were investigated.Results:1) Compared with the N group,rats with MS exhibited higher SBP, FBS, FINS, HOMA-IR, TG, TC, LDL-C, HDL-C, FFA, ALT, Aspartic Transaminase(AST), UA, Blood Urea Nitrogen (BUN), Carnine(CR)(P<0.01or<0.05), expression of NF-κB、MCP-1、ED-1(P<0.01), but lower weight (P<0.01).There were also intima media thickening and structural disorder in rats with MS.2) Compared with the M group, rats in F group exhibited higher HDL-C,AST (P<0.01) and lower TG, LDL-C, FFA (P<0.01or<0.05), SBP, FINS, HOMA-IR (P<0.01), UA, CR (P<0.01or<0.05),expression of NF-κB,MCP-1,ED-1(P<0.01), and thinner intima-media thickness and less artery structural disorder.3) Compared with the M group, rats in P group exhibited higher HDL-C (P<0.01), UA (P<0.05) and lower TG, TC, LDL-C, FFA (P<0.01or<0.05), SBP, FBS, FINS, HOMA-IR (P<0.01or<0.05), expression of NF-κB,MCP-1,ED-1,(P<0.05). Compared with the F group, rats in P group exhibited higher FBS, FINS, HOMA-IR (P<0.01) and lower expression of NF-κB,MCP-1,ED-1(P<0.01). Compared with the M or F group,rats in P group exhibited thinner intima-media thickness and less aortic structural disorder.4) Compared with the M group, rats in F+P group exhibited lower blood pressure, lipids, blood glucose, FINS, HOMA-IR, UA, CR(P<0.01or<0.05), but higher HDL-C, AST (P<0.05or<0.05), and lower expression of NF-κB,MCP-1,ED-1. Compared with the F group, rats in F+P group exhibited lower TC, HDL-C, SBP, FBS, FINS,HOMA-IR (P<0.01) and expression of NF-κB,MCP-1,ED-1(P<0.01or<0.05). Compared with the P group, rats leveling F+P group exhibited higher HDL-C (P<0.01) and lower UA (P<0.01), expression of NF-κB,MCP-1,ED-1(P<0.05). Compared with all the other intervention groups, rats in F+P group exhibited thinnest intima-media thickness and least aortic structure disorder.Conclusions:1) The combined used of fenofibrate and pioglitazone was more effective than using them alone in improving high blood pressure,the metabolism of lipid and glucose, insulin resistance and artery lesions in rats with MS.2) Expression of the NF-κB, MCP-1, ED-1were significantly increased in rats with MS. The combination of fenofibrate and pioglitazone has beneficial effects in decreasing expression of NF-κB、MCP-1、ED-1in artery.3) Evidence has been shown in the study that the combination of fenofibrate and pioglitazone protected the renal function, but damaged the liver function. Background:The combined application of PPAR-a and PPAR-y agonists demonstrated better effect in improving the metabolism of blood glucose, blood lipid and IR, lowering the expression of PPAR-a/ymRNA, and relieving the inflammatory state in MS rat model in part2of this study. We hereby continue to investigate the protection effect of combined application of PPAR-a and PPAR-y agonists on atherosclerosis of carotid artery. Atherosclerosis of carotid artery can reflect the atherosclerosis of artery in other part of the body, such as coronary artery, cerebral artery. CRP and MMP-9which were identified as indicator of inflammatory and intimately relevant to atherosclerosis, were selected as parameters in this part of study.Objectives:To study the effect of combined use of PPAR-a and PPAR-y agonists on the IMT and positive rate of arterial plague of carotid artery in patients with MS.Methods:242patients with MS and30healthy adults were included in the study. Patients were randomly assigned to the Basic treatment group (B group, n=60), Fenofibrate group (F group, n=61), Pioglitazone group (P group, n=61), and Fenofibrate+Pioglitazone group (F+P group, n=60). The healthy adults were assigned to the control group (C group, n=30) All patients were given lifestyle interventions and medication treatment to control blood pressure, blood glucose, and blood lipid Additionally, Patients in F group took fenofibrate0.2g/day. Patients in P group took pioglitazone15mg/day. Patieints in F+P group took both fenofibrate0.2g/day and pioglitazone15mg/day. The intervention lasted for24weeks. The treatment groups and control group were comparatively studied on blood pressure, blood glucose (BG), blood lipids, serum concentration of hsCRP and,MMP-9, Intima Media Thickness (IMT) of the carotid artery and positive rates of carotid arterial plaques.Results:1) Compared with the N group, patients with MS exhibited higher blood pressure, FBG, FINS, HOME-IR, Total Lipids (TL), Low Density Lipoprotein (LDL), triglyeride (TG), Free Fatty Acid (FFA), Alanine Aminotransferase (ALT), Uric Acid (UA), hsCRP, MMP-9, IMT of the carotid artery and positive rate of carotid arterial plaques.2) Compared with the B Group, patients in F group exhibited lower TG, FFA, FINS (P<0.05) and higher High Density Lipoprotein (HDL)(P <0.05); patients in P group exhibited lower TG, FFA, HbAlc, FINS, hsCRP, MMP-9, HOME-IR, IMT of the carotid artery and positive rate of carotid arterial plaques (P<0.05); patient in F+P group exhibited lower TG, FFA, HbAlc, FINS, hsCRP, MMP-9(P<0.01or<0.05), DBP, HOME-IR, IMT of the carotid artery and positive rate carotid arterial plaques (P<0.05). 3) Compared with the F group, patients in P group exhibited lower FINS, hsCRP, MMP-9, HOME-IR, positive rate of carotid arterial plaques (P<0.01or P<0.05); patients in F+P group exhibited lower FINS, hsCRP, MMP-9(P<0.01or P<0.05), HOME-IR, IMT of the carotid artery and positive rate of carotid arterial plaques (P<0.01or P<0.05).4) Compared with the P group, patients in F+P group exhibited higher HDL (P<0.05) and lower IMT of the carotid artery (P<0.05).Conclusions:1) Patients with MS exhibited elevated IR, hsCRP, MMP-9, increased IMT of the carotid artery and higher positive rate of carotid arterial plaques.2) Fenofibrate in addition to basic treatment has beneficial effect on improving the metabolism of FFA and TG, and decreasing hsCRP and MMP-9in patients with MS.3) Pioglitazone in addition to basic treatment has beneficial effect on improving IR and blood pressure, and decreasing hsCRP, MMP-9, IMT of the carotid artery and positive rate of carotid arterial plaques.4) In this study, the combination of pioglitazone and fenofibrate in addition to basic treatment has been the most effective treatment in improving IR, hsCRP, and MMP-9, and decreasing IMT of the carotid artery and positive carotid artery plaques. |
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