PPAR-α/γ激动剂联合应用对代谢综合征动脉粥样硬化的保护机制研究
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摘要
背景：代谢综合征(metabolic syndrome, MS)作为一种以高血压、糖代谢异常、血脂代谢紊乱和肥胖为特征的综合征,聚集了致动脉粥样硬化的血脂异常、血压增高、胰岛素抵抗、糖耐量异常、促血栓及促凝状态等多种危险因素,已成为动脉粥样硬化的高危因素之一。过氧化物酶体增殖物激活受体-α/γ(peroxisome proliferator activated receptor-α/γ,PPAR-α/γ)激动剂可以通过不同的作用机制改善代谢综合征患者的糖脂代谢紊乱和亚临床炎症状态,发挥抗动脉粥样硬化的作用而广受关注。目前临床上多以单独应用为主,我们推测两类药物联合应用对于代谢综合征所导致的动脉粥样硬化可能有更好的保护作用,因而进行了本研究。我们拟建立代谢综合征大鼠模型,观察PPAR-α激动剂非诺贝特和PPAR-γ激动剂吡格列酮单独和联合干预对大鼠模型的主动脉的保护作用并探讨其可能的机制。高果糖饮食诱导SD大鼠建立的代谢综合征模型具有成模时间短、价格便宜、更接近现实生活中代谢综合征的发病机制等特点,因此我们选择建立高果糖饮食诱导的代谢综合征模型。
目的：采用高果糖饮食诱导,建立SD大鼠代谢综合征模型,观察其血糖、血脂代谢特点和主动脉病变情况。
方法：SD大鼠60只,随机抽出10只作为对照组(C组,n=10),用普通大鼠饲料喂养。其余50只作为代谢综合征模型组(M组,n=50),用高果糖饲料喂养,两组大鼠均分笼喂养10周。观察两组大鼠的体重、尾动脉血压、FBS、FINS、TC、TG、LDL-C、HDL-C、FFA、ALT、AST、BUN、CR、UA的变化特点,计算其HOMA-IR,同时观察大鼠主动脉的形态学变化。
结果：造模过程中,M组大鼠尾动脉血压到第4周末高于C组,至第8周末显著高于C组；M组大鼠FBS于第10周开始高于C组；血清FINS水平于第4周开始高于C组,至第8周显著高于C组；HOMA-IR于第4周显著高于C组；M组大鼠血清TG水平至第4周高于C组,至第8周显著高于C组；血清TC水平至第4周高于C组,至第10周显著高于C组；血清LDL-C水平至第4周高于C组,至第10周显著高于C组；血清FFA水平至第4周高于C组,至第8周显著高于C组；血清HDL-C水平到第10周高于对照组；M组大鼠至第8周血清ALT、AST及UA水平高于对照组,到第10周血清BUN、CR水平也高于对照组。与C组相比M组大鼠主动脉内膜结构紊乱,不均匀增厚,内弹力膜有不同程度破坏、断裂,中膜层增厚,弹力纤维结构紊乱,平滑肌细胞增生,并向内膜增生,内中膜增厚。
结论：1)高果糖饮食诱导的代谢综合征大鼠模型建模成功,该模型显示出高血压、高胰岛素血症、胰岛素抵抗、高甘油三脂血症、高血清游离脂肪酸等代谢综合征的特征性改变,并出现肝肾功能的损害。2)代谢综合征大鼠模型存在主动脉粥样硬化改变。
背景：在第一部分的研究中我们建立了代谢综合征大鼠模型,该模型显示出了高血压、高胰岛素血症、胰岛素抵抗、高甘油三脂血症、高血清游离脂肪酸等代谢综合征的特征性改变,并出现了动脉粥样硬化改变,可以用来进一步研究PPAR-α激动剂非诺贝特和PPAR-γ激动剂吡格列酮单独和联合应用对代谢综合征大鼠主动脉的保护作用。单核巨噬细胞在动脉粥样硬化的发生发展中的发挥着重要作用,MCP-1作为一种趋化因子,不但可以促进单核细胞在粥样斑块处的聚集,还可促使血管平滑肌细胞的增殖,参与动脉粥样硬化的发病。NF-κB可调控编码MCP-1基因,破坏血管内皮结构和功能的完整性,参与动脉血管壁粥样斑块的形成。所以我们选取以上三个指标作为观察对象,观察PPAR-α/γ激动剂对代谢综合征大鼠主动脉的炎症指标的影响。
目的：观察联合应用非诺贝特和吡格列酮干预对代谢综合征大鼠模型的体重、尾动脉血压、血脂代谢、血糖代谢、胰岛素抵抗的影响和大鼠主动脉NF-κB、MCP-1、ED-1的表达,探讨PPAR-α/γ激动剂联合应用对代谢综合征大鼠模型动脉粥样硬化的保护机制。
方法：代谢综合征模型大鼠42只,随机分为模型对照组(M组,n=10)、非诺贝特组(F组,n=11)、吡格列酮组(P组,n=10)、非诺贝特+匹格列酮组(F+P组,n=11),普通标准饲料喂养的SD大鼠为空白对照组州组,n=6)。F组加用非诺贝特30mg/kg,P组大鼠加用吡格列酮3mg/kg,F+P组大鼠同时加用相同剂量的非诺贝特和吡格列酮,给药方法为溶于水中灌胃,每日一次,共4周；干预前后测定大鼠体重、尾动脉血压、血糖、FINS、HOMA-IR、血脂、肝肾功能。4周后处死大鼠,检测其主动脉形态结构和主动脉NF-κB、MCP-1、ED-l的表达。分析比较干预后各组大鼠在上述指标间的差异及关系。
结果：1)与N组大鼠相比：代谢综合征大鼠尾动脉血压、FBS、FINS、HOMA-IR、TG、TC、LDL-C、HDL-C、FFA,ALT、AST、UA、BUN、CR水平升高(P<0.01或P<0.05),体重减轻(P<0.01),主动脉表达NF-κB、MCP-1、ED-1表达升高(P均<0.01),主动脉内中膜增厚、结构紊乱
2)与M组大鼠相比：F组大鼠尾动脉血压、FINS、HOMA-IR、TG、LDL-C、FFA、UA、CR降低(P<0.01或<0.05),HDL-C、AST升高(P均<0.01)；主动脉NF-κB、MCP-1、ED-1表达下调(P均<0.01),主动脉内中膜变薄,内中膜结构有所改善。
3)与M大鼠相比：P组大鼠血清尾动脉血压、FBS、FINS、 HOMA-IR、TG、TC、LDL-C、FFA降低(P<0.01或<0.05),HDL-C升高(P<0.01)；主动脉NF-κB、MCP-1、ED-1表达下调(P<0.01或<0.05)；与F组大鼠比较：P组大鼠FBS、FINS、HOMA-IR降低(P均<0.01),血清UA升高(P<0.05),主动脉NF-κB、MCP-1、ED-1表达降低(P<0.01)；主动内中膜较M组及F组大鼠变薄,结构更为完整有序。
4)与M大鼠相比：F+P组大鼠血清尾动脉血压、FBS、FINS、 HOMA-IR、TG、TC、LDL-C、FFA、UA、CR降低(P<0.01或<0.05),HDL-C、AST升高(P<0.01或<0.05)；主动脉NF-κB、MCP-1、ED-1表达下调；与F组大鼠相比：血清TC降低,HDL-C升高,尾动脉血压、FBS、FINS、HOMA-IR降低(P均<0.01),主动脉NF-κB、MCP-1、ED-1表达下调(P<0.01或P<0.05)；与P组大鼠比较,F+P组大鼠血清HDL-C升高(P<0.01),血清UA降低(P<0.01),NF-κB、MCP-1、ED-1表达下调(P<0.05)；大鼠主动脉内中膜厚度及结构等方面较其它干预组均改善。
结论：1)联合应用非诺贝特和吡格列酮比单独使用更能有效改善代谢综合征大鼠模型的高血压、脂代谢紊乱、糖代谢异常、胰岛素抵抗及动脉病变。
2)代谢综合征大鼠模型的主动脉表达NF-κB、MCP-1、ED-1显著增加。联合用药比单独用药更能降低主动脉NF-κB、MCP-1、ED-1的表达。
3)动物实验显示,非诺贝特和吡格列酮联合干预对肾功能存在保护作用,但对肝功能有损害作用。
背景：在第二章的研究中,我们通过动物实验证实PPAR-α/γ激动剂联合应用可更好的改善代谢综合征大鼠模型的血脂、血糖代谢和胰岛素抵抗状态,降低PPAR-α/γmRNA和蛋白表达水平,减轻亚临床炎症反应,从而更有效的发挥抗动脉粥样硬化的作用。我们拟通过临床观察,了解两类药物单独和联合应用对于代谢综合征患者动脉粥样硬化的保护作用的差别。颈动脉粥样硬化可间接反应冠状动脉、脑动脉以及其他部位动脉粥样硬化的程度和范围,且可作为动脉粥样硬化的独立预测因子,C-反应蛋白和MMP-9作为敏感的炎症反应指标,与动脉粥样硬化有着密切的关系,所以我们选择以上指标作为观察指标。
目的：探讨PPAR-α、PPAR-γ激动剂联合干预对代谢综合征患者颈总动脉IMT及斑块阳性率的影响。
方法：选取代谢综合征患者242例及健康对照者30例为研究对象,代谢综合征患者随机分为基础治疗组(B组,n=60)、非诺贝特组(F组,n=61)、吡格列酮组(P组,n=61)、非诺贝特+吡格列酮组(F+P组,n=60),健康对照者为正常对照组(N组,n=30)。F组加服非诺贝特,P组加服吡格列酮,F+P组同时加服上述两种药物,共干预24周。分析比较干预后组间血压、血糖、血脂、hsCRP、MMP-9、颈总动脉IMT、颈总动脉粥样斑块阳性率的差异。
结果：1)与N组健康者相比：代谢综合征患者血压、FBS、FINS. HOME-IR、TC、LDL-C、TG、FFA、ALT、UA、hsCRP、MMP-9水平升高,颈总动脉IMT及斑块阳性率也升高(P<0.01或P<0.05)。
2)与B组患者相比,F组患者血清TG、FFA、FINS水平降低(P<0.01或P<0.05),HDL-C水平升高(P<0.05)；P组患者血清TG、FFA、HbAlc、FINS、hsCRP、MMP-9水平降低,HOME-IR、颈总动脉IMT及斑块阳性率降低(P<0.01或P<0.05)；F+P组患者血清TG、FFA、HbAlc、FINS、hsCRP、MMP-9水平降低(P<0.01或P<0.05),DBP、HOME-IR、颈总动脉IMT及斑块阳性率降低(P<0.05)。
3)与F组患者相比,P组患者血清FINS、hsCRP、MMP-9水平降低,HOME-IR及颈总动脉斑块阳性率降低(P<0.01或P<0.05)；F+P组患者血清FINS.hsCRP、MMP-9水平降低(P<0.01或P<0.05),HOME-IR、颈总动脉IMT及斑块阳性率降低(P<0.01或P<0.05)。
4)与P组患者相比,F+P组患者血清HDL-C水平升高(P<0.05),颈总动脉IMT降低(P<0.05)。
结论：1)代谢综合征患者存在胰岛素抵抗,血清CRP、MMP-9水平升高,颈总动脉IMT增厚、斑块阳性率升高。
2)基础治疗加用非诺贝特可改善代谢综合征患者FFA、TG代谢,降低血清CRP、MMP-9水平。
3)基础治疗加用吡格列酮可改善代谢综合征患者的胰岛素抵抗、尾动脉血压,降低血清hsCRP、MMP-9水平,降低其颈总动脉斑块阳性率。
4)基础治疗加用非诺贝特和吡格列酮可更为有效地改善代谢综合征患者的胰岛素抵抗,降低血清hsCRP、MMP-9水平,改善颈总动脉IMT,降低颈总动脉斑块阳性率。
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.
目的：采用高果糖饮食诱导,建立SD大鼠代谢综合征模型,观察其血糖、血脂代谢特点和主动脉病变情况。
方法：SD大鼠60只,随机抽出10只作为对照组(C组,n=10),用普通大鼠饲料喂养。其余50只作为代谢综合征模型组(M组,n=50),用高果糖饲料喂养,两组大鼠均分笼喂养10周。观察两组大鼠的体重、尾动脉血压、FBS、FINS、TC、TG、LDL-C、HDL-C、FFA、ALT、AST、BUN、CR、UA的变化特点,计算其HOMA-IR,同时观察大鼠主动脉的形态学变化。
结果：造模过程中,M组大鼠尾动脉血压到第4周末高于C组,至第8周末显著高于C组；M组大鼠FBS于第10周开始高于C组；血清FINS水平于第4周开始高于C组,至第8周显著高于C组；HOMA-IR于第4周显著高于C组；M组大鼠血清TG水平至第4周高于C组,至第8周显著高于C组；血清TC水平至第4周高于C组,至第10周显著高于C组；血清LDL-C水平至第4周高于C组,至第10周显著高于C组；血清FFA水平至第4周高于C组,至第8周显著高于C组；血清HDL-C水平到第10周高于对照组；M组大鼠至第8周血清ALT、AST及UA水平高于对照组,到第10周血清BUN、CR水平也高于对照组。与C组相比M组大鼠主动脉内膜结构紊乱,不均匀增厚,内弹力膜有不同程度破坏、断裂,中膜层增厚,弹力纤维结构紊乱,平滑肌细胞增生,并向内膜增生,内中膜增厚。
结论：1)高果糖饮食诱导的代谢综合征大鼠模型建模成功,该模型显示出高血压、高胰岛素血症、胰岛素抵抗、高甘油三脂血症、高血清游离脂肪酸等代谢综合征的特征性改变,并出现肝肾功能的损害。2)代谢综合征大鼠模型存在主动脉粥样硬化改变。
背景：在第一部分的研究中我们建立了代谢综合征大鼠模型,该模型显示出了高血压、高胰岛素血症、胰岛素抵抗、高甘油三脂血症、高血清游离脂肪酸等代谢综合征的特征性改变,并出现了动脉粥样硬化改变,可以用来进一步研究PPAR-α激动剂非诺贝特和PPAR-γ激动剂吡格列酮单独和联合应用对代谢综合征大鼠主动脉的保护作用。单核巨噬细胞在动脉粥样硬化的发生发展中的发挥着重要作用,MCP-1作为一种趋化因子,不但可以促进单核细胞在粥样斑块处的聚集,还可促使血管平滑肌细胞的增殖,参与动脉粥样硬化的发病。NF-κB可调控编码MCP-1基因,破坏血管内皮结构和功能的完整性,参与动脉血管壁粥样斑块的形成。所以我们选取以上三个指标作为观察对象,观察PPAR-α/γ激动剂对代谢综合征大鼠主动脉的炎症指标的影响。
目的：观察联合应用非诺贝特和吡格列酮干预对代谢综合征大鼠模型的体重、尾动脉血压、血脂代谢、血糖代谢、胰岛素抵抗的影响和大鼠主动脉NF-κB、MCP-1、ED-1的表达,探讨PPAR-α/γ激动剂联合应用对代谢综合征大鼠模型动脉粥样硬化的保护机制。
方法：代谢综合征模型大鼠42只,随机分为模型对照组(M组,n=10)、非诺贝特组(F组,n=11)、吡格列酮组(P组,n=10)、非诺贝特+匹格列酮组(F+P组,n=11),普通标准饲料喂养的SD大鼠为空白对照组州组,n=6)。F组加用非诺贝特30mg/kg,P组大鼠加用吡格列酮3mg/kg,F+P组大鼠同时加用相同剂量的非诺贝特和吡格列酮,给药方法为溶于水中灌胃,每日一次,共4周；干预前后测定大鼠体重、尾动脉血压、血糖、FINS、HOMA-IR、血脂、肝肾功能。4周后处死大鼠,检测其主动脉形态结构和主动脉NF-κB、MCP-1、ED-l的表达。分析比较干预后各组大鼠在上述指标间的差异及关系。
结果：1)与N组大鼠相比：代谢综合征大鼠尾动脉血压、FBS、FINS、HOMA-IR、TG、TC、LDL-C、HDL-C、FFA,ALT、AST、UA、BUN、CR水平升高(P<0.01或P<0.05),体重减轻(P<0.01),主动脉表达NF-κB、MCP-1、ED-1表达升高(P均<0.01),主动脉内中膜增厚、结构紊乱
2)与M组大鼠相比：F组大鼠尾动脉血压、FINS、HOMA-IR、TG、LDL-C、FFA、UA、CR降低(P<0.01或<0.05),HDL-C、AST升高(P均<0.01)；主动脉NF-κB、MCP-1、ED-1表达下调(P均<0.01),主动脉内中膜变薄,内中膜结构有所改善。
3)与M大鼠相比：P组大鼠血清尾动脉血压、FBS、FINS、 HOMA-IR、TG、TC、LDL-C、FFA降低(P<0.01或<0.05),HDL-C升高(P<0.01)；主动脉NF-κB、MCP-1、ED-1表达下调(P<0.01或<0.05)；与F组大鼠比较：P组大鼠FBS、FINS、HOMA-IR降低(P均<0.01),血清UA升高(P<0.05),主动脉NF-κB、MCP-1、ED-1表达降低(P<0.01)；主动内中膜较M组及F组大鼠变薄,结构更为完整有序。
4)与M大鼠相比：F+P组大鼠血清尾动脉血压、FBS、FINS、 HOMA-IR、TG、TC、LDL-C、FFA、UA、CR降低(P<0.01或<0.05),HDL-C、AST升高(P<0.01或<0.05)；主动脉NF-κB、MCP-1、ED-1表达下调；与F组大鼠相比：血清TC降低,HDL-C升高,尾动脉血压、FBS、FINS、HOMA-IR降低(P均<0.01),主动脉NF-κB、MCP-1、ED-1表达下调(P<0.01或P<0.05)；与P组大鼠比较,F+P组大鼠血清HDL-C升高(P<0.01),血清UA降低(P<0.01),NF-κB、MCP-1、ED-1表达下调(P<0.05)；大鼠主动脉内中膜厚度及结构等方面较其它干预组均改善。
结论：1)联合应用非诺贝特和吡格列酮比单独使用更能有效改善代谢综合征大鼠模型的高血压、脂代谢紊乱、糖代谢异常、胰岛素抵抗及动脉病变。
2)代谢综合征大鼠模型的主动脉表达NF-κB、MCP-1、ED-1显著增加。联合用药比单独用药更能降低主动脉NF-κB、MCP-1、ED-1的表达。
3)动物实验显示,非诺贝特和吡格列酮联合干预对肾功能存在保护作用,但对肝功能有损害作用。
背景：在第二章的研究中,我们通过动物实验证实PPAR-α/γ激动剂联合应用可更好的改善代谢综合征大鼠模型的血脂、血糖代谢和胰岛素抵抗状态,降低PPAR-α/γmRNA和蛋白表达水平,减轻亚临床炎症反应,从而更有效的发挥抗动脉粥样硬化的作用。我们拟通过临床观察,了解两类药物单独和联合应用对于代谢综合征患者动脉粥样硬化的保护作用的差别。颈动脉粥样硬化可间接反应冠状动脉、脑动脉以及其他部位动脉粥样硬化的程度和范围,且可作为动脉粥样硬化的独立预测因子,C-反应蛋白和MMP-9作为敏感的炎症反应指标,与动脉粥样硬化有着密切的关系,所以我们选择以上指标作为观察指标。
目的：探讨PPAR-α、PPAR-γ激动剂联合干预对代谢综合征患者颈总动脉IMT及斑块阳性率的影响。
方法：选取代谢综合征患者242例及健康对照者30例为研究对象,代谢综合征患者随机分为基础治疗组(B组,n=60)、非诺贝特组(F组,n=61)、吡格列酮组(P组,n=61)、非诺贝特+吡格列酮组(F+P组,n=60),健康对照者为正常对照组(N组,n=30)。F组加服非诺贝特,P组加服吡格列酮,F+P组同时加服上述两种药物,共干预24周。分析比较干预后组间血压、血糖、血脂、hsCRP、MMP-9、颈总动脉IMT、颈总动脉粥样斑块阳性率的差异。
结果：1)与N组健康者相比：代谢综合征患者血压、FBS、FINS. HOME-IR、TC、LDL-C、TG、FFA、ALT、UA、hsCRP、MMP-9水平升高,颈总动脉IMT及斑块阳性率也升高(P<0.01或P<0.05)。
2)与B组患者相比,F组患者血清TG、FFA、FINS水平降低(P<0.01或P<0.05),HDL-C水平升高(P<0.05)；P组患者血清TG、FFA、HbAlc、FINS、hsCRP、MMP-9水平降低,HOME-IR、颈总动脉IMT及斑块阳性率降低(P<0.01或P<0.05)；F+P组患者血清TG、FFA、HbAlc、FINS、hsCRP、MMP-9水平降低(P<0.01或P<0.05),DBP、HOME-IR、颈总动脉IMT及斑块阳性率降低(P<0.05)。
3)与F组患者相比,P组患者血清FINS、hsCRP、MMP-9水平降低,HOME-IR及颈总动脉斑块阳性率降低(P<0.01或P<0.05)；F+P组患者血清FINS.hsCRP、MMP-9水平降低(P<0.01或P<0.05),HOME-IR、颈总动脉IMT及斑块阳性率降低(P<0.01或P<0.05)。
4)与P组患者相比,F+P组患者血清HDL-C水平升高(P<0.05),颈总动脉IMT降低(P<0.05)。
结论：1)代谢综合征患者存在胰岛素抵抗,血清CRP、MMP-9水平升高,颈总动脉IMT增厚、斑块阳性率升高。
2)基础治疗加用非诺贝特可改善代谢综合征患者FFA、TG代谢,降低血清CRP、MMP-9水平。
3)基础治疗加用吡格列酮可改善代谢综合征患者的胰岛素抵抗、尾动脉血压,降低血清hsCRP、MMP-9水平,降低其颈总动脉斑块阳性率。
4)基础治疗加用非诺贝特和吡格列酮可更为有效地改善代谢综合征患者的胰岛素抵抗,降低血清hsCRP、MMP-9水平,改善颈总动脉IMT,降低颈总动脉斑块阳性率。
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.
引文
[1]Keller KB, Lemberg L. Obesity and the metabolic syndrome [J]. Am J Crit Care,2003,12:167-170
[2]Zambon A, Gervois P, Pauletto P, et al. Modulation of hepatic inflammatory risk markers of cardiovascular diseases by PPAR-alpha activators:clinical and experiment-tal evidence [J].Arterioscler Thromb Vase Bio J 2006,26:977-986
[3]Chinetti G, Griglio S, Antonucei M, et al. Activation of proliferactor activated receptors aand y induces apoptosis of human monocyte-derivedmacrophages [J].BiolChem,1998,237(40):25575-25580.
[4]Tordjman K, Bernal-Mizrachi C, Zemany L, et al. PPAR alpha deficiency reduces insulin resistance and atherosclerosis in apoE-null mice [J]. J Clin Invest, 2001,107:1025-1034
[5]Mardones P, Pilon A, Bouly M, et al. Fibrates down-regulate hepatic scavenger receptor class B type I protein expression in mice [J]. J Biol Chem,2003,278:7884-7890.
[6]Ricote M, Li AC, Willson TM, et al. The peroxisome proliferator activated Rece-ptor-y is a negative regulator of macrophage activation [J]. Nature,1998,391:79-82.
[7]Moore MC, Cherrington AD, Mann SL, et al. Acute fructose administration decreases the glycemic response to an oral glucose tolerance test in normal adults [J]. J Clin Endocrinol Metab,2000,85(12):4515-419
[8]Stanhope KL,Schwarz JM, Keim NL, et al. Consuming fructose sweetened, not glucose-sweetened, beverages increases visceral adiposity and lipids and decreases insulin sensitivity in overweight/obese humans [J]. J Clin Invest,2009, 119:1322-1334
[9]Laura G, Sanchez-Lozada, Edilia Tapia, et al. Fructose-induced metabolic syndro-me is associated with glomerular hypertension and renal microvascular damage inrats [J]. Am J Physiol Ren 1 Physiol,2007(2),292:423-429
[10]Hwang IS, Ho H, Hoffman BB, et al. Fructose-induced insulin resistance and hypertension in rats [J]. Hypertension,1987,10 (5):512-516
[11]Hwang IS, Ho H, Hoffman BB, et al. Fructose-induced insulin resistance and hypertension in rats [J]. Hypertension,1987,10 (5):512-516
[12]李斌,余绮玲,钟向红.2型糖尿病伴冠心病患者胰岛素抵抗与游离脂肪酸关系研究[J].临床荟萃,2008,23(1)：13～15
[13]Hennes MI, Dua A, Kissehah AH. Effects of free fatty acids and glucose on splan chnic insulin dynamics [J]. Diabetes,1997,46(1):57-62
[14]Tripathy D, Mohanty P, Dhindsa S, et al. Elevation of free fatty acids induces inflammation and impairs vascular reactivity in healthy subjects [J]. Diabetes, 2003,52(12):2882-2887
[15]Burke JR. Targeting I kappa B kinase for the treatment of inflammatory and other disorders [J].Curr Opin Drug Discov Devel [J].2003,6(5):720-728
[16]Sun Y, Liu S, Ferguson S, et al. Phosphoenolpyruvate carboxy kinase overexpre-ssion selectively attenuates insulin signaling and hepatic insulin sensitivity in transg-enic mice [J]. J Biol Chem,2002,277(26):23301-23307
[17]Virkamaki A, Korsheninnikova E, Seppala-Lindroos A, et al. Intramyo cellular lipid is associated with resistance to in vivo insulin actions on glucose uptake, antilipolysis, and early insulin signaling pathways in human skeletal muscle [J]. Diabetes 2001,50(10):2337-2343
[18]Haffner SM. Themetabolic syndrome:inflammation, diabetes melli-tus, and cardiovascular disease [J].Am J Cardio,l 2006,97(2A):3A-11A.
[19]Yuan M, Konstantopoulos N, Lee J, et al. Reversal of obesity and diet induced insulin resistance with salicylates or targeted disruption of IKKb [J]. Science, 2001,293(5535):1673-1677
[20]Moore MC, Cherrington AD, Mann SL, et al. Acute fructose administration decreases the glycemic response to an oral glucose tolerance test in normal adults [J]. J Clin Endocrinol Metab,2000,85(12):4515-419
[21]Bantle JP. Dietary Fructose and Metabolic Syndrome and Diabetes [J]. J Nutr, 2009,139(6):1263-1268
[22]Robbez Masson V, Lucas A, Gueugneau AM, et al. Long-chain (n-3) polyunsatu-rated fatty acids prevent metabolic and vascular disorders in fructose-fedrats [J]. J Nutr,2008,138(10):1915-1922
[23]李怡,吴翥镗,刘震等.高果糖饲料诱导的胰岛素抵抗伴高血压大鼠模型及其特点[J].中国比较医学杂志,2004,14(4)：211～214
[24]Schwartz MW, Woods SC, Porte D Jr, et al. Central nervous system control of food intake [J]. Nature,2000,404:661-671
[25]Takagawa Y, Berger ME, Hori MT, et al. Long-term fructose feeding impairs vascular relaxation in rat mesenteric arteries [J]. Am J Hypertens 2001,14 (8 Pt 2):811-817
[26]Giacchetti G, Sechi LA, Griffin CA, et al. The tissue renin-angiotensin system in rats with fructose-induced hypertension:over expression of type 1 angiotensin II rece-ptor in adipose tissue [J]. J Hypertens 2000,18(5):695-702
[27]Coates PA, Luzio SD, Brunel P, et al. Comparison of estimates of insulin sensiti-vity from minimal model analysis of the insulin-modified frequently, sampled intrav-enous glucose tolerance test and the isoglycemic hyper insulinemic clamp in subjects with NIDDM [J]. Diabetes,1995,44(6):631-635
[28]De Fronzo RA, Tobin JD, Andres R. Glucose clamp technique:a method for quantifying insulin secretion and resistance [J]. Am J Physiol,1979,237(3): 214-223
[29]张家庆.怎样检测胰岛素抵抗[J].中华医学杂志,2005,85(35)：2454～2456
[30]夏燕萍,陈刚,俞茂华.高糖高脂饮食诱导建立SD大鼠代谢综合征模型[J].中国现代医学杂志,2009,19(17)：55～57
[31]余海峰,陈黎.代谢综合征与肾功能相关性分析[J].中国医师进修杂志,2006,29(10)：41～43
[32]张曙云,黄龚,俞小忠等.肝功能异常与代谢综合征的关系[J].中国慢性病预与控制,2008,16(4)：393～395
[33]Nakagawa T, Hu H, Zharikov S, et al. A causal role for uric acid in fructose-induced metabolic syndrome [J]. Am J Physiol Renal Physiol,2006, 290(3):625-631
[34]张莉莉,王利娟,曹廷兵等.代谢综合征和自发性高血压大鼠血管结构及功能差异的研究[J].解放军医学杂志,2005,30(8)：706～708
[1]闫振成.PPARs在代谢综合征心血管损害中作用的临床和实验研究：[博士学位论文].重庆：第三军医大学,2004
[2]Guerre-Millo M, Gervois P, Raspe E, et al. Peroxisome proliferator-activated receptor alpha activators improve insulin sensitivity and reduce adiposity. J Biol Chem,2000,275(22):16638-16642
[3]Duez H, Chao YS, Hernandez M, et al. Reduction of atherosclerosis by the peroxisome proliferative-activated receptor alpha agonist fenofibrate in mice. J Biol Chem,2002,277(50):48051-48057
[4]Li AC, Brown KK, Silvestre MJ, et al. Peroxisome proliferator-activated receptor γ ligands inhibit development of atherosclerosis in LDL receptor-deficient mice. J Clin Invest,2000,106(4):523-531
[5]Li AC, Binder CJ, Gutierrez A, et al. Differential inhibition of macrophage foam-cell formation and atherosclerosis in mice by PPARα, β/δ, and γ. J Clin Invest,2004,114(11):1564-1576
[6]Han SH, Quon MJ, Koh KK. Beneficial vascular and metabolic effects of perox-isome proliferator--activated receptor-alpha activators [J]. Hypertension, 2005,46(5):1086-1089
[7]Koh KK, Han SH, Qon MJ, et al. Beneficial effects of fenefibrate to improve endothelial dysfunction and raise adiponectin levels in patients witll primary hypert-riglye-eridemia[J]. Diabetes Care,2005,28(6):1419-22
[8]李传保,卜培莉,张运等.非诺贝特对hsCRP自发性高血压大鼠心肌重构及NF-KB的表达[J].山东大学学报(医学版),2007,45(1)：46～48
[9]DE Dios ST, Hannan KM, Dilley RJ, et al. Troglitazone, but not rosiglitazone inhibits Na/H exchange activity and proliferation of macrovascular endothelial cells[J]. J Diabetes Complications,2001,15(3):120-127
[10]Sugawara A, Takeuchi K, Uruno A,et al. Transcriptional suppression of type 1 ceptor2gamma in vascular smooth muscle cells [J]. Endocrinology,2001,142 (7):3125-3134
[11]Hsueh WA, Jackson S, Law RE. Control of vascular cell proliferation and migra-tion by PPAR-gamma:a new approach to the macrovascular complications of diabe-tes [J]. Diabetes Care,2001,24(2):392-397
[12]Benson S, Wu J, Padmanabhan S, et al. Peroxisome proliferator activated receptor (PPAR)-gamma expression in human vascular smooth muscle cells:inhibition of growth, migration, and c-fos expression by the peroxisome proliferator activated receptor (PPAR)-gamma activator troglitazone [J]. Am J Hypertens,2000, 13:74-82
[13]马雅銮,蔺洁,秦明照等.单核-巨噬细胞亚型与动脉粥样硬化[J].中华临床医师杂志(电子版),2010,4(5)：658～660
[14]Ross R. Atherosclerosis an inflammatory disease [J]. N Engle J Med,1999,340(2): 115-126
[15]Gonzalez Quesada C, Franqoqiannis NG. Monocyte chemo attractant protein-1/CCL2 as a biomarker in acute coronary syndromes [J]. Curr Atheroscler Rep,2009,11(2):131-138
[16]Martinovlc I, Abegunewardene N, Seul M, et al. Elevated monocyte chemoa-ttractant protein-1 serum levels in patients at risk for coronary artery disease [J]. Circ J,2005,69:1484-1489
[17]Delerive P,Martin-Nizard F,Chinetti G,et al. PPAR activators inhibit thrombin-induced endothelin-1 production in human vascular endothelial cells by inhibiting the AP-1 signalling pathway [J].Circ Res,1999,85:394-402
[18]Ozcan U, Cao Q, Yilmaz E, et al. Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science,2004,306 (5695):457-461
[19]Han S, Liang CP, DeVries-Seimon T, et al. Macrophage insulin receptor deficiency increases ER stress-induced apoptosis and necrotic core formation in advanced atherosclerotic lesions. Cell Metab,2006,3(4):257-266
[20]Sangnino E, Bojarano R, Vazquez CM, et al. Increased triglyceride burden in old rats is originated by sex-related changes in liver expression of PPARa and biosynthetic enzymes. Proceedings of Second International Symposium on PPARs. Florence, Italy 2003,30
[21]Neve BP, Fruchart JC, Staels B. Role of the peroxisome proliferator activated receptors (PPAR) in atherosclerosis. Biochem Pharmacol,2000,60:1245-1250
[22]Quy N.Diep, Ernesto L. Schiffrin.Increased expression of peroxisome proliferatoractivated receptor-α and-γ in blood vessels of spontaneously hypertensive rats.Hypertension,2001,38:249-254
[23]Schaiff W T, Carlson M G, et al. The activity of PPAR gamma in primary human trophoblasts is enhanced by oxidized lipid. Clin Endocrinol Metab,2002,87(3): 1105-1129
[24]Orasanu G, Ziouzenkova O, Devchand PR, et al. The peroxisome proliferator-activated receptor-gamma agonist pioglitazone represses inflammation in a peroxisome proliferator-activated receptor-alpha-dependent manner in vitro and in vivo in mice. J Am Coll Cardiol,2008,52(10):869-881
[25]Hema S, Bagry, MD. Metabolic Syndrome and Insulin Resistance [J]. Anesthesiology,2008; 108:506-512
[26]Marx N, Sukhova GK, Collins T, et al. PPARalpha agonists inhibit cytokine-induced vascular cell adhesion molecule-1 expression in human endothelial cells [J]. Circulation,1999,99(24):3125-3131
[27]Zahradka P,Wright B,Fuerst M,et al.Peroxisome proliferators-activated receptor alpha and gamma ligands differentially affect smooth muscle cell proliferation and migration [J]. J Pharmacol Exp Ther,2006,317:651-659
[28]Li AC, Binder CJ,Gutierrez A,et al.Differential inhibition of macrophage foam-cell formation and atherosclerosis in mice by PPARalpha,beta/delta,and gamma [J]. JClin Invest,2004,114:1564-1576
[29]Reifel-Miller A, Otto K, Hawkins E, et al. A peroxisome proliferators-activated receptor dual agonist with a unique in vitro profile and potent glucose and lipid effects in rodent models of type 2 diabetes and dyslipidemia [J]. Molecular Endocrinology,2005,19(6):1593-1605
[30]Neve BP, Fruchart JC, Staels B. Role of the peroxisome proliferator activated receptors (PPAR) in atherosclerosis [J]. Biochem Pharmacol,2000,60:1245-1250
[31]Quy N.Diep, Ernesto L. Schiffrin.Increased expression of peroxisome prolifera-toractivated receptor-α and-γ in blood vessels of spontaneously hypertensiverats [J].Hypertension,2001,38:249-254
[32]Schaiff WT, Carlson MG, et al. The activity of PPAR gamma in primary human trophoblasts is enhanced by oxidized lipid [J]. Clin Endocrinol Metab,2002,87(3): 1105-1129
[33]何媛媛,李素梅,叶山东.核因子KB与代谢综合征关系的研究进展[J].国际内科学杂志,2008,35(3)：147～150
[34]冯罡,孙玥,孙侃.单核细胞趋化蛋白-1与2型糖尿病大血管病变[J].现代生物医学进展,2010,10(3)：578～579
[35]Schmitz G, Grandl M. Role of redox regulation and lipid rafts in macrophages during Ox-LDL-mediated foam cell formation [J]. Antioxid Redox Signal,2007, 9(9):1499-1518
[36]Amirbekian V, Lipinski MJ, Briley-Seabo KC, et al. Detecting and assessing macrophages in vivo to evaluate atherosclerosis noninvasively using molecular MRI[J]. Proc Natl Acad Sci USA,2007,104(3):961-966
[37]Tordjman K, Bernal-Mizrachi C, Zemany L, et al. PPAR alpha deficiency reduces insulin resistance and atherosclerosis in apoE-null mice [J]. J Clin Invest, 2001,107:1025-1034
[1]Ross R. Atherosclerosis-an inflammatory disease [J].N Engl J Med,1999,340(2): 115-126
[2]陈雅琴,赵水平.C-反应蛋白与动脉粥样硬化--谁才是始作俑者[J].医学与哲学(临床决策论坛版),2010,31(4)：39～41
[3]王磊,马依彤.基质金属蛋白酶-9与动脉粥样硬化及斑块稳定性的研究进展[J].中国循证心血管医学杂志,2010,2(2)：108～111
[4]张妍,黄磊,刘金玲.2型糖尿病简易胰岛素抵抗测定方法的比较研究[J].天津医科大学学报,2005,11(4)：560～562
[5]邹密,蒋利,钟健等.非糖尿病代谢综合征与颈动脉粥样硬化的研究[J].中华老年心脑血管病杂志,2007,9(5)：323～325
[6]赵志钢,罗志丹,祝之明.代谢综合征患者尿微量白蛋白与颈动脉粥样硬化的关系[J].中华高血压杂志,2006,14(2)：97-101
[7]赵志钢,祝之明,李彦社.代谢综合征的颈动脉粥样硬化特征[J].中华内科杂志,2003,42(9)：625-627
[8]赵家军,韩文霞,管庆波.代谢综合征研究进展[J].山东医药,2005,45(25)：77～79
[9]Sukru C, Turan E, Hasan K, et al. Carotid intima-media thickness in patients with isolated coronary artery ectasia [J]. Atherosclerosis,2006,3(1):1-3
[10]Marit G, Marjut V. Association of carotid intima-media thickness with angio graphic severity and extent of coronary artery disease [J]. Am J Cardiol,2006,97 (5):624-629
[11]Mule G, Cottone S, Mongiovi R, et al. Influence of the. metabolic syndrome on aortic stiffness in never treated hypertensive patients [J]. Nut r-Metab-Cardiovasc Dis[J].2006,16(1):54-59
[12]吴升,张曙云,徐晓峰.军队离退休干部代谢综合征患病率与动脉粥样硬化的相关性[J].中国老年医学杂志,2010,30(15)：2107～2108
[13]Haffner SM. Themetabolic syndrome:inflammation, diabetesmellitus, and cardio-vascular disease [J]. Am J Cardio,2006,97(2):3-11
[14]Paul A, Ko KW, Li L, et al. C-reactive protein accelerates the progression of atherosclerosis in apolipoprotein E-deficientmice [J]. Circulation,2004,109(5): 647-655
[15]Han KH, Hong KH, Park JH, et al. C-reactive protein promotesmonocyte Chemo-attractant protein 1-mediated chemotaxis through upregulating CC chemokine recap-tor 2 expression in human monocytes [J]. Circulation,2004, 109(21):2566-571
[16]Galis ZS, Johnson C, Godin D, et al. Targeted disruption of the matrix metal proteinase-9 gene impairs smooth muscle cell migration and geometrical arterial remodeling [J]. Circ Res,2002,91(9):852-859
[17]侯振江,张宗英.基质金属蛋白酶类测定的临床应用[J].中国实验诊断学,2006,10(2)：216～218
[18]李永明,赵瑞平.基质金属蛋白酶-9与心血管疾病[J].内蒙古医学杂志,2008,40(7)：843～845
[19]余丹青,陈纪言,李光等.基质金属蛋白酶与冠状动脉粥样硬化斑块稳定性相关研究[J].中国循环杂志,2003,18(2)：105～107
[1]Marx N,Duez H, Fruchart JC,et al.Peroxisome proliferator-activated receptors and atherogenesis regulators of gene expression in vascular cells [J]. CircRes, 2004,94(9):1168-1178.
[2]张慧灵,顾振纶,秦正红.PPARs与神经退行性疾病[J].中国药理学通报,2006,22(4)：397-402.
[3]Guan Y,ZhangY,BreyerMD.The Role of PPARs in the Transcriptional Control of Cellular Processes[J].Drug News Perspect,2002,15:147-154.
[4]Chinetti G,Fruchart JC,Staels B.Peroxisome proliferator-ativated receptors (PPARs):nuclear receptors at the crossroads between lipidmetabolism and inflammation[J].Inflamm Res,2000,49(10):497-505.
[5]Libby P.Inflammation in atherosclerosis[J].Nature,2002,420:868-874.
[6]Zambon A,Gervois P,Pauletto P,et al.Modulation of hepatic inflammatory risk markers of cardiovascular diseases by PPAR-alpha activators:clinical and experimental evidence[J].Arterioscler Thromb Vase Bio J 2006,26:977-986.
[7]Chinetti G,Griglio S,Antonucei M,et al.Activation of proliferactor activated receptors α and γ induces apoptosis of human monocyte derived macrophages [J].Biol Chem,1998,237(40):25575-25580.
[8]Tordjman K,Bernal-Mizrachi C,Zemany L,et al.PPAR alpha deficiency reduces insulin resistance and atherosclerosis in apoE-null mice[J].J Clin Invest,2001, 107:1025-1034.
[9]Mardones P,Pilon A,Bouly M,et al.Fibrates down-regulate hepatic scavenger receptor class B type I protein expression in mice[J].J Biol Chem,2003,278: 7884-7890.
[10]Devchand PR,Keller H,Peters JM,et al.The PPARa-leukotriene B4 pathway to inflammation control[J].Nature,1996,384:39-43.
[11]Delerive P,Bosscher KD,Besnard S,et al.Peroxisome proliferators-activated receptor-α negatively regulates the vascular inflammatory gene response by negative Cross-talk with transcription factors NF-κB and AP-1[J].J Biol Chem,1999,274:32-48.
[12]Delerive P,Martin-Nizard F,Chinetti G,et al. PPAR activators inhibit thrombin-induced endothelin-1 production in human vascular endothelial cells by inhibiting the AP-1 signalling pathway[J].Circ Res,1999,85:394-402.
[13]Marx N,Sukhova GK,Collins T,et al.PPARalpha agonists inhibit cytokine-induced vascular cell adhesion molecule-1 expression in human endothelial cells [J].Circulation,1999,99(24):3125-3131.
[14]陈丽红,杨光锐,管又飞.PPARα、PPARγ及其双激动剂与动脉粥样硬化[J].生理科学进展,2007,38(2)：153-155.
[15]Vosper H,Khoudoli G,Graham T,et al.Peroxisome proliferators activated receptor agonists, hyperlipidaemia and Atherosclerosis[J]. Pharmacol Ther,2002,95(1): 47-62.
[16]Gervois P,Torra I,Fruchart JC,et al.Regulation of lipid andlipoprotein metabolism by PPAR activator[J].Clin Chem Lab Med,2000,38(1):3-11.
[17]Xu XP,Meisel SR,Ong JM,et al.Oxidized low-density lipoprotein regulates matrix metalloproteinae-9 and its tissue inhibitor in human monocyte-derived macrophages[J].Circulation,1999,99(8):993-998.
[18]Eberhardt W,Akoolel S,Rebhan J,et al.Inhibition of cytokine-induced matrixmetalloproteinase 9 expression by peroxisome proliferator-activated receptor alpha agonists is in directand due to a NO-mediated reduction of mRNA stability[J]J BiolChem,2002,277(36):33518-33528.
[19]Ricote M,Li AC,Willson TM,et al.The peroxisome proliferator-activated receptor-γ is a negative regulator of macrophage activation [J]. Nature,1998, 391:79-82.
[20]Ishibashi M,Egashira K,Hiase K,et al.Anti-inflammatory and anti-arteriosclerotic effects of pioglitazone [J].Hypertension,2002,40(5):687-693.
[21]Chun SW, Kang BY,Kim SH,et al.Oxidized low density lipoprotein inhibits interleukin-12 production in lipopolysacchride-activated mouse macrophages viadirect interactions between PPARγ and NF-κB[J].J Biol Chem,2000, 276(32):681-687.
[22]Daynes RA,Jones DC.Emerging roles of PPARs in inflammation and immunity [J].Nat Rev Immuno J,2002,2(10):748-759.
[23]Yang XY,Wang LH,Chen T,et al.Activation of human T lymphocytes is inhibited by peroxisome proliferator2activated receptor γ (PPAR γ) agonists[J].J Biol Chem,2000,275(4):541-544.
[24]Bouhlel MA,Derudas B,Rigamonti E,et al.PPARgamma activationprimes human monocytes into alternative M2 macrophages with anti inflammatory properties[J].Cell Metab,2007,6(2):137-143.
[25]Nagy L,Tontonoz P,Alvarez JGA,et al.Oxidized LDL regulates macrophage gene exression through ligand activation of PPAR γ [J].Cell,1998,93:229-240.
[26]Tontonoz P,Nagy L,Alvarez JGA,et al.PPAR γ promotes moocyte/macrophage differentiation and uptake of oxidized LDL[J].Cell,1998,93:241-252.
[27]Argmann CA,Sawyez CG,McNeil CJ,et al.Activation of peroxisome proliferator-activated receptor gamma and retinoid X receptor results in net depletion of cellular cholesteryl esters in macrophages exposed to oxidized lipoproteins[J].Arterioscler Thromb Vasc Biol,2003,23(3):475-482.
[28]Francis GA,Fayard E,Picard F,et al.Nuclear receptors and the control of metabolism[J].Annu Rev Physiol,2003,65:261-311.
[29]Larsen TM,Toubro S,Astrup A.PPAR gamma agonists in the treatment of type Ⅱ diabetes:is increased fatness commensurate with long-term efficacy[J].Int J Obes Relat Metab Disord,2003,27(2):147-161.
[30]Shibasaki M,Takahashi K,Itou T,et al.A PPAR agonist improves TNF-a induced insulin resistance of adipose tissue in mice[J].Biochem Biophy Res Commu,2003,309(2):419-424.
[31]Meredith D,Panchatcharam M.Dominant-negative loss of PPAR-gamma function enhances smooth muscle cell proliferation,migration, and vascular remodeling[J].Arterioscler Thromb Vase Bio J,2009,29(4):465-471.
[32]SooL,Cheng JJ,Min K,et al.PPARgamma gene transfer sustains apoptosis, inhibits vascular smooth muscle cell proliferation, and reduces neointima formation after balloon injury in rats[J].Arterioscler Thromb Vase Bio J.2006,26(4):808-813.
[33]Goetze S,Xi XP,Kawano H,et al.PPAR-ligands inhibit migration mediated by multiple chemoattractants in vascular smooth muscle cells[J]. J Cardiovasc Pharmacol.1999,33:798-806.
[34]Marx N,Schonbeck U,Lazar MA,et al.Peroxisome proliferator-activated receptor activators inhibit gene expression and migration in human vascular smooth muscle cells[J].Circ Res.1998,83:1097-1103.
[35]Forman BM,Tontonoz P,Chen J,et al.15-Deoxy-delta-12,14-prostaglandin J2 is a ligand for the adipocyte determination factor PPAR gamma [J]. Cell,1995, 83:803-812.
[36]Tontonoz P,Nagy L,Alvarez JGA,et al.PPAR γ promotes moocyte/macrophage differentiation and uptake of oxidized LDL[J].Cell,1998,93:241-252.
[37]Krey G,Braissant O,L'Horset F,et al.Fatty acids, eicosanoids, and hypolipidemic agents identified as ligands of peroxisome proliferator-activated receptors by co-activator-dependent receptor ligand assay [J].Mol Endcrinol,1997,11:779-791.
[38]Robins SJ,Collins D,Wittes JT,et al.Relation of gemfibrozil8 treatment and lipid levels with major coronary events[J].J Am Med Assoc,2001,285:1585-1591.
[39]Grossman SL,Lessem J.Mechanisms and clinical effects of thiazolidinediones [J]. Exp Opin Invest Drugs,1997,6:1025-40.
[40]Lehmann JM,Oliver BB,Ringold GM,et al.Peroxisome proliferator-activated receptors α and β are activated by indomethacin and other non-sterooidal anti-inflammatoru drugs[J].J Biol Chem,1997,79:81-94.
[41]Buckle DR,Cantello,BCC,Cawthorne,MA,et al.Non thiazolidine-dione antihyperglycaemic agents:a-Heteroatom substitutedβ-phenylpropanoic acids[J]. Bioorganic and Medicinal Chem Lett.1996,6(17):2121-2130.
[42]Brook DA,Etgen GJ,Rito CJ,et al.Design and synthesis of 2-methyl-2-{4-[2-(5-methyl-2-aryloxazol-4-yl) ethoxy]phenoxy}-pro-pionic acids:A new class of dual PPAR α/γ agonists[J].J Med Chem,2001,44:2061-2064.
[43]Ushiroda K,Maruta K,Takazawa T,et al.Synthesis and Pharmaco-logical Evaluation of Novel Benzoylazole-Based PPARα/γ Activators[J].Bioorganic & Medicinal Chemistry Letters,2011,doi:10.1016/j.bmcl.2011.02.032.
[44]DAIS.Effect of fenofibrate on progression of coronary-artery disease in type 2 diabetes:the DiabetesAtherosclerosis Intervention Study,a randomised study[J].Lancet,2001,357(9260):905-910.
[45]Staels B,Koening W,Habib A,et al. Activation of human aortic smooth muscle cell is inhibited by PPARα but not by PPARγ activators[J]. Nature,1998, 393:790.
[46]Madej A,Okopien B,Kowalski J,et al.Effects of fenofibrate on plasma cytokine concentrations in patients with atherosclerosis and hyperlipoproteinemia Ⅱ b[J].Int J Pharmacol Thera,1998,36:345-349.
[47]Ferreira AV,Parreira GG,Green A,etal.Effects of fenofibrate on lipidmetabolism in adipose tissue of rats[J].Metabolism,2006,55(6):731-5.
[48]Delerive P,Gervois P,Fruchart JC,et al.Induction of κ IB α expression as a mechanism contributing to the anti2inflammatory activities of PPAR a activators[J].J Biol Chem,2000,27(36):703-707.
[49]周晓惠,王佑民,王文平等.吡格列酮和非诺贝特对高脂饲养大鼠脂联素与胰岛素抵抗的影响[J].安徽医科大学学报,2008,43(4)：418-421.
[50]Oki K,Koide J,Nakanishi S,et al.Fenofibrate increases high molecular weight adiponectin in subjects with hypertriglyceridemi[J].Endocr J,2007,54(3):431-5.
[51]Mangan S,Clancy P,Golledge J.Modulation of endothelial cell thrombomodulin by PPAR ligands-Variation according to environment [J].Thromb Res,2007,13[Epub ahead ofprint].
[52]Sidhu JS,Kaposzta Z,MarkusHS,et al.Effect of rosiglitazone on common carotid intima-media thickness progression in coronary artery disease patientswithout diabetesmellitus[J].Arteriosclerosis Thrombosis & Vascular Biology,2004,24(5): 930-934.
[53]Kang QH,Chen AP,Jawahar.S1896 curcumin inhibits Ox-LDL-activated hepatic stellate cells in vitro by suppressing gene expression of lectin-like oxidized-LDL receptor via activation of peroxisome proliferator-activated receptor-gamma [J].Gastroenterology,2008,134 (4):A-779.
[54]Spanheimer R,Betteridge J,Tan MH,et al.Long-term lipid effects of pioglitazone by baseline anti-hyperglycemia medication therapy and statin use from the PROactive experience (PROactive 14)[J].The American Journal of Cardiology, 2009,104(2):234-239.
[55]Davidson M,Meyer PM,Haffner S,et al.Increased high-density lipoprotein cholesterol predicts the pioglitazone-mediated reduetionof carotid intima-media thickness progression in patientswith type 2 diabete smellitus[J]. Circulation, 2008,117:2123-2130.
[56]楚罗香,姜德谦,刘照云.吡格列酮对人脐静脉内皮细胞CD40/CD40L表达的影响[J].中国药物与临床,2006,6(1)：48-51.
[57]Horio T,Suzuki M,Takamisawa I,et al.Pioglitazone-induced insulin sensitization improves vascular endothelial function in nondiabetic patients with essential hypertension[J].Am J Hypertens,2005,18:1626-1630.
[58]Benomar Y,Roy AF,Aubourg A,et al.Cross down-regulation ofLeptin and insulin receptor expression and signalling in a human neuronal cell line [J]. Biochem, 2005,388:929-939.
[59]Ruiz E,Redondo S,Gordillo-Moscoso A,et al.Pioglitazone induces apoptosis in human vascular smoothmuscle cells from diabetic patients involving the transforming growthfactor-beta/activin receptor-like inase-4/5/7/Smad2 signaling pathway [J].Pharmacol Exp Ther,2007,321(2):431-438.
[60]袁晓晨,刘乃丰,严金川等.过氧化物酶体增殖物激活受体γ对糖基化终产物诱导大鼠血管平滑肌细胞增殖的作用[J].中华心血管病杂志,2005,33(10)：940-944.
[61]Gensch C,CleverY,WernerC,et al.The PPAR-yagonistpioglitazone increases neoangiogenesis and prevents apoptosis of endothelial progenitor cells[J] Atherosclerosis,2007,192:67-74.
[62]Werner C,Kamani CH,Gensh C,et al.The peroxisome proliferator-activated receptor-gamma agonist pioglitazone increases number and function of endothelial progenitor cells in patients with coronary artery disease and normal glucose tolerance [J]. Diabetes,2007,56 (10):2609-2615.
[63]骆雷鸣,朱启伟.苯扎贝特对高甘油三酯血症患者脂代谢及糖代谢的影响[J].中国实用内科杂志,2009,29(4)：1-4.
[64]Zahradka P,Wright B,Fuerst M,et al.Peroxisome proliferators-activated receptor alpha and gamma ligands differentially affect smooth muscle cell proliferation and migration[J].J PharmacolExp Ther,2006,317:651-659.
[65]Li AC, Binder CJ,Gutierrez A,et al.Differential inhibition of macrophage foam-cell formation and atherosclerosis in mice by PPARalpha,beta/delta,and gamma[J].J Clin Invest,2004,114:1564-1576.
[66]Reifel-Miller A,Otto K,Hawkins E,et al.A peroxisome proliferators-activated receptor dual agonist with a unique in vitro profile and potent glucose and lipid effects in rodent models of type 2 diabetes and dyslipidemia[J].Molecular Endocrinology,2005.19 (6):1593-1605.
[2]Zambon A, Gervois P, Pauletto P, et al. Modulation of hepatic inflammatory risk markers of cardiovascular diseases by PPAR-alpha activators:clinical and experiment-tal evidence [J].Arterioscler Thromb Vase Bio J 2006,26:977-986
[3]Chinetti G, Griglio S, Antonucei M, et al. Activation of proliferactor activated receptors aand y induces apoptosis of human monocyte-derivedmacrophages [J].BiolChem,1998,237(40):25575-25580.
[4]Tordjman K, Bernal-Mizrachi C, Zemany L, et al. PPAR alpha deficiency reduces insulin resistance and atherosclerosis in apoE-null mice [J]. J Clin Invest, 2001,107:1025-1034
[5]Mardones P, Pilon A, Bouly M, et al. Fibrates down-regulate hepatic scavenger receptor class B type I protein expression in mice [J]. J Biol Chem,2003,278:7884-7890.
[6]Ricote M, Li AC, Willson TM, et al. The peroxisome proliferator activated Rece-ptor-y is a negative regulator of macrophage activation [J]. Nature,1998,391:79-82.
[7]Moore MC, Cherrington AD, Mann SL, et al. Acute fructose administration decreases the glycemic response to an oral glucose tolerance test in normal adults [J]. J Clin Endocrinol Metab,2000,85(12):4515-419
[8]Stanhope KL,Schwarz JM, Keim NL, et al. Consuming fructose sweetened, not glucose-sweetened, beverages increases visceral adiposity and lipids and decreases insulin sensitivity in overweight/obese humans [J]. J Clin Invest,2009, 119:1322-1334
[9]Laura G, Sanchez-Lozada, Edilia Tapia, et al. Fructose-induced metabolic syndro-me is associated with glomerular hypertension and renal microvascular damage inrats [J]. Am J Physiol Ren 1 Physiol,2007(2),292:423-429
[10]Hwang IS, Ho H, Hoffman BB, et al. Fructose-induced insulin resistance and hypertension in rats [J]. Hypertension,1987,10 (5):512-516
[11]Hwang IS, Ho H, Hoffman BB, et al. Fructose-induced insulin resistance and hypertension in rats [J]. Hypertension,1987,10 (5):512-516
[12]李斌,余绮玲,钟向红.2型糖尿病伴冠心病患者胰岛素抵抗与游离脂肪酸关系研究[J].临床荟萃,2008,23(1)：13～15
[13]Hennes MI, Dua A, Kissehah AH. Effects of free fatty acids and glucose on splan chnic insulin dynamics [J]. Diabetes,1997,46(1):57-62
[14]Tripathy D, Mohanty P, Dhindsa S, et al. Elevation of free fatty acids induces inflammation and impairs vascular reactivity in healthy subjects [J]. Diabetes, 2003,52(12):2882-2887
[15]Burke JR. Targeting I kappa B kinase for the treatment of inflammatory and other disorders [J].Curr Opin Drug Discov Devel [J].2003,6(5):720-728
[16]Sun Y, Liu S, Ferguson S, et al. Phosphoenolpyruvate carboxy kinase overexpre-ssion selectively attenuates insulin signaling and hepatic insulin sensitivity in transg-enic mice [J]. J Biol Chem,2002,277(26):23301-23307
[17]Virkamaki A, Korsheninnikova E, Seppala-Lindroos A, et al. Intramyo cellular lipid is associated with resistance to in vivo insulin actions on glucose uptake, antilipolysis, and early insulin signaling pathways in human skeletal muscle [J]. Diabetes 2001,50(10):2337-2343
[18]Haffner SM. Themetabolic syndrome:inflammation, diabetes melli-tus, and cardiovascular disease [J].Am J Cardio,l 2006,97(2A):3A-11A.
[19]Yuan M, Konstantopoulos N, Lee J, et al. Reversal of obesity and diet induced insulin resistance with salicylates or targeted disruption of IKKb [J]. Science, 2001,293(5535):1673-1677
[20]Moore MC, Cherrington AD, Mann SL, et al. Acute fructose administration decreases the glycemic response to an oral glucose tolerance test in normal adults [J]. J Clin Endocrinol Metab,2000,85(12):4515-419
[21]Bantle JP. Dietary Fructose and Metabolic Syndrome and Diabetes [J]. J Nutr, 2009,139(6):1263-1268
[22]Robbez Masson V, Lucas A, Gueugneau AM, et al. Long-chain (n-3) polyunsatu-rated fatty acids prevent metabolic and vascular disorders in fructose-fedrats [J]. J Nutr,2008,138(10):1915-1922
[23]李怡,吴翥镗,刘震等.高果糖饲料诱导的胰岛素抵抗伴高血压大鼠模型及其特点[J].中国比较医学杂志,2004,14(4)：211～214
[24]Schwartz MW, Woods SC, Porte D Jr, et al. Central nervous system control of food intake [J]. Nature,2000,404:661-671
[25]Takagawa Y, Berger ME, Hori MT, et al. Long-term fructose feeding impairs vascular relaxation in rat mesenteric arteries [J]. Am J Hypertens 2001,14 (8 Pt 2):811-817
[26]Giacchetti G, Sechi LA, Griffin CA, et al. The tissue renin-angiotensin system in rats with fructose-induced hypertension:over expression of type 1 angiotensin II rece-ptor in adipose tissue [J]. J Hypertens 2000,18(5):695-702
[27]Coates PA, Luzio SD, Brunel P, et al. Comparison of estimates of insulin sensiti-vity from minimal model analysis of the insulin-modified frequently, sampled intrav-enous glucose tolerance test and the isoglycemic hyper insulinemic clamp in subjects with NIDDM [J]. Diabetes,1995,44(6):631-635
[28]De Fronzo RA, Tobin JD, Andres R. Glucose clamp technique:a method for quantifying insulin secretion and resistance [J]. Am J Physiol,1979,237(3): 214-223
[29]张家庆.怎样检测胰岛素抵抗[J].中华医学杂志,2005,85(35)：2454～2456
[30]夏燕萍,陈刚,俞茂华.高糖高脂饮食诱导建立SD大鼠代谢综合征模型[J].中国现代医学杂志,2009,19(17)：55～57
[31]余海峰,陈黎.代谢综合征与肾功能相关性分析[J].中国医师进修杂志,2006,29(10)：41～43
[32]张曙云,黄龚,俞小忠等.肝功能异常与代谢综合征的关系[J].中国慢性病预与控制,2008,16(4)：393～395
[33]Nakagawa T, Hu H, Zharikov S, et al. A causal role for uric acid in fructose-induced metabolic syndrome [J]. Am J Physiol Renal Physiol,2006, 290(3):625-631
[34]张莉莉,王利娟,曹廷兵等.代谢综合征和自发性高血压大鼠血管结构及功能差异的研究[J].解放军医学杂志,2005,30(8)：706～708
[1]闫振成.PPARs在代谢综合征心血管损害中作用的临床和实验研究：[博士学位论文].重庆：第三军医大学,2004
[2]Guerre-Millo M, Gervois P, Raspe E, et al. Peroxisome proliferator-activated receptor alpha activators improve insulin sensitivity and reduce adiposity. J Biol Chem,2000,275(22):16638-16642
[3]Duez H, Chao YS, Hernandez M, et al. Reduction of atherosclerosis by the peroxisome proliferative-activated receptor alpha agonist fenofibrate in mice. J Biol Chem,2002,277(50):48051-48057
[4]Li AC, Brown KK, Silvestre MJ, et al. Peroxisome proliferator-activated receptor γ ligands inhibit development of atherosclerosis in LDL receptor-deficient mice. J Clin Invest,2000,106(4):523-531
[5]Li AC, Binder CJ, Gutierrez A, et al. Differential inhibition of macrophage foam-cell formation and atherosclerosis in mice by PPARα, β/δ, and γ. J Clin Invest,2004,114(11):1564-1576
[6]Han SH, Quon MJ, Koh KK. Beneficial vascular and metabolic effects of perox-isome proliferator--activated receptor-alpha activators [J]. Hypertension, 2005,46(5):1086-1089
[7]Koh KK, Han SH, Qon MJ, et al. Beneficial effects of fenefibrate to improve endothelial dysfunction and raise adiponectin levels in patients witll primary hypert-riglye-eridemia[J]. Diabetes Care,2005,28(6):1419-22
[8]李传保,卜培莉,张运等.非诺贝特对hsCRP自发性高血压大鼠心肌重构及NF-KB的表达[J].山东大学学报(医学版),2007,45(1)：46～48
[9]DE Dios ST, Hannan KM, Dilley RJ, et al. Troglitazone, but not rosiglitazone inhibits Na/H exchange activity and proliferation of macrovascular endothelial cells[J]. J Diabetes Complications,2001,15(3):120-127
[10]Sugawara A, Takeuchi K, Uruno A,et al. Transcriptional suppression of type 1 ceptor2gamma in vascular smooth muscle cells [J]. Endocrinology,2001,142 (7):3125-3134
[11]Hsueh WA, Jackson S, Law RE. Control of vascular cell proliferation and migra-tion by PPAR-gamma:a new approach to the macrovascular complications of diabe-tes [J]. Diabetes Care,2001,24(2):392-397
[12]Benson S, Wu J, Padmanabhan S, et al. Peroxisome proliferator activated receptor (PPAR)-gamma expression in human vascular smooth muscle cells:inhibition of growth, migration, and c-fos expression by the peroxisome proliferator activated receptor (PPAR)-gamma activator troglitazone [J]. Am J Hypertens,2000, 13:74-82
[13]马雅銮,蔺洁,秦明照等.单核-巨噬细胞亚型与动脉粥样硬化[J].中华临床医师杂志(电子版),2010,4(5)：658～660
[14]Ross R. Atherosclerosis an inflammatory disease [J]. N Engle J Med,1999,340(2): 115-126
[15]Gonzalez Quesada C, Franqoqiannis NG. Monocyte chemo attractant protein-1/CCL2 as a biomarker in acute coronary syndromes [J]. Curr Atheroscler Rep,2009,11(2):131-138
[16]Martinovlc I, Abegunewardene N, Seul M, et al. Elevated monocyte chemoa-ttractant protein-1 serum levels in patients at risk for coronary artery disease [J]. Circ J,2005,69:1484-1489
[17]Delerive P,Martin-Nizard F,Chinetti G,et al. PPAR activators inhibit thrombin-induced endothelin-1 production in human vascular endothelial cells by inhibiting the AP-1 signalling pathway [J].Circ Res,1999,85:394-402
[18]Ozcan U, Cao Q, Yilmaz E, et al. Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science,2004,306 (5695):457-461
[19]Han S, Liang CP, DeVries-Seimon T, et al. Macrophage insulin receptor deficiency increases ER stress-induced apoptosis and necrotic core formation in advanced atherosclerotic lesions. Cell Metab,2006,3(4):257-266
[20]Sangnino E, Bojarano R, Vazquez CM, et al. Increased triglyceride burden in old rats is originated by sex-related changes in liver expression of PPARa and biosynthetic enzymes. Proceedings of Second International Symposium on PPARs. Florence, Italy 2003,30
[21]Neve BP, Fruchart JC, Staels B. Role of the peroxisome proliferator activated receptors (PPAR) in atherosclerosis. Biochem Pharmacol,2000,60:1245-1250
[22]Quy N.Diep, Ernesto L. Schiffrin.Increased expression of peroxisome proliferatoractivated receptor-α and-γ in blood vessels of spontaneously hypertensive rats.Hypertension,2001,38:249-254
[23]Schaiff W T, Carlson M G, et al. The activity of PPAR gamma in primary human trophoblasts is enhanced by oxidized lipid. Clin Endocrinol Metab,2002,87(3): 1105-1129
[24]Orasanu G, Ziouzenkova O, Devchand PR, et al. The peroxisome proliferator-activated receptor-gamma agonist pioglitazone represses inflammation in a peroxisome proliferator-activated receptor-alpha-dependent manner in vitro and in vivo in mice. J Am Coll Cardiol,2008,52(10):869-881
[25]Hema S, Bagry, MD. Metabolic Syndrome and Insulin Resistance [J]. Anesthesiology,2008; 108:506-512
[26]Marx N, Sukhova GK, Collins T, et al. PPARalpha agonists inhibit cytokine-induced vascular cell adhesion molecule-1 expression in human endothelial cells [J]. Circulation,1999,99(24):3125-3131
[27]Zahradka P,Wright B,Fuerst M,et al.Peroxisome proliferators-activated receptor alpha and gamma ligands differentially affect smooth muscle cell proliferation and migration [J]. J Pharmacol Exp Ther,2006,317:651-659
[28]Li AC, Binder CJ,Gutierrez A,et al.Differential inhibition of macrophage foam-cell formation and atherosclerosis in mice by PPARalpha,beta/delta,and gamma [J]. JClin Invest,2004,114:1564-1576
[29]Reifel-Miller A, Otto K, Hawkins E, et al. A peroxisome proliferators-activated receptor dual agonist with a unique in vitro profile and potent glucose and lipid effects in rodent models of type 2 diabetes and dyslipidemia [J]. Molecular Endocrinology,2005,19(6):1593-1605
[30]Neve BP, Fruchart JC, Staels B. Role of the peroxisome proliferator activated receptors (PPAR) in atherosclerosis [J]. Biochem Pharmacol,2000,60:1245-1250
[31]Quy N.Diep, Ernesto L. Schiffrin.Increased expression of peroxisome prolifera-toractivated receptor-α and-γ in blood vessels of spontaneously hypertensiverats [J].Hypertension,2001,38:249-254
[32]Schaiff WT, Carlson MG, et al. The activity of PPAR gamma in primary human trophoblasts is enhanced by oxidized lipid [J]. Clin Endocrinol Metab,2002,87(3): 1105-1129
[33]何媛媛,李素梅,叶山东.核因子KB与代谢综合征关系的研究进展[J].国际内科学杂志,2008,35(3)：147～150
[34]冯罡,孙玥,孙侃.单核细胞趋化蛋白-1与2型糖尿病大血管病变[J].现代生物医学进展,2010,10(3)：578～579
[35]Schmitz G, Grandl M. Role of redox regulation and lipid rafts in macrophages during Ox-LDL-mediated foam cell formation [J]. Antioxid Redox Signal,2007, 9(9):1499-1518
[36]Amirbekian V, Lipinski MJ, Briley-Seabo KC, et al. Detecting and assessing macrophages in vivo to evaluate atherosclerosis noninvasively using molecular MRI[J]. Proc Natl Acad Sci USA,2007,104(3):961-966
[37]Tordjman K, Bernal-Mizrachi C, Zemany L, et al. PPAR alpha deficiency reduces insulin resistance and atherosclerosis in apoE-null mice [J]. J Clin Invest, 2001,107:1025-1034
[1]Ross R. Atherosclerosis-an inflammatory disease [J].N Engl J Med,1999,340(2): 115-126
[2]陈雅琴,赵水平.C-反应蛋白与动脉粥样硬化--谁才是始作俑者[J].医学与哲学(临床决策论坛版),2010,31(4)：39～41
[3]王磊,马依彤.基质金属蛋白酶-9与动脉粥样硬化及斑块稳定性的研究进展[J].中国循证心血管医学杂志,2010,2(2)：108～111
[4]张妍,黄磊,刘金玲.2型糖尿病简易胰岛素抵抗测定方法的比较研究[J].天津医科大学学报,2005,11(4)：560～562
[5]邹密,蒋利,钟健等.非糖尿病代谢综合征与颈动脉粥样硬化的研究[J].中华老年心脑血管病杂志,2007,9(5)：323～325
[6]赵志钢,罗志丹,祝之明.代谢综合征患者尿微量白蛋白与颈动脉粥样硬化的关系[J].中华高血压杂志,2006,14(2)：97-101
[7]赵志钢,祝之明,李彦社.代谢综合征的颈动脉粥样硬化特征[J].中华内科杂志,2003,42(9)：625-627
[8]赵家军,韩文霞,管庆波.代谢综合征研究进展[J].山东医药,2005,45(25)：77～79
[9]Sukru C, Turan E, Hasan K, et al. Carotid intima-media thickness in patients with isolated coronary artery ectasia [J]. Atherosclerosis,2006,3(1):1-3
[10]Marit G, Marjut V. Association of carotid intima-media thickness with angio graphic severity and extent of coronary artery disease [J]. Am J Cardiol,2006,97 (5):624-629
[11]Mule G, Cottone S, Mongiovi R, et al. Influence of the. metabolic syndrome on aortic stiffness in never treated hypertensive patients [J]. Nut r-Metab-Cardiovasc Dis[J].2006,16(1):54-59
[12]吴升,张曙云,徐晓峰.军队离退休干部代谢综合征患病率与动脉粥样硬化的相关性[J].中国老年医学杂志,2010,30(15)：2107～2108
[13]Haffner SM. Themetabolic syndrome:inflammation, diabetesmellitus, and cardio-vascular disease [J]. Am J Cardio,2006,97(2):3-11
[14]Paul A, Ko KW, Li L, et al. C-reactive protein accelerates the progression of atherosclerosis in apolipoprotein E-deficientmice [J]. Circulation,2004,109(5): 647-655
[15]Han KH, Hong KH, Park JH, et al. C-reactive protein promotesmonocyte Chemo-attractant protein 1-mediated chemotaxis through upregulating CC chemokine recap-tor 2 expression in human monocytes [J]. Circulation,2004, 109(21):2566-571
[16]Galis ZS, Johnson C, Godin D, et al. Targeted disruption of the matrix metal proteinase-9 gene impairs smooth muscle cell migration and geometrical arterial remodeling [J]. Circ Res,2002,91(9):852-859
[17]侯振江,张宗英.基质金属蛋白酶类测定的临床应用[J].中国实验诊断学,2006,10(2)：216～218
[18]李永明,赵瑞平.基质金属蛋白酶-9与心血管疾病[J].内蒙古医学杂志,2008,40(7)：843～845
[19]余丹青,陈纪言,李光等.基质金属蛋白酶与冠状动脉粥样硬化斑块稳定性相关研究[J].中国循环杂志,2003,18(2)：105～107
[1]Marx N,Duez H, Fruchart JC,et al.Peroxisome proliferator-activated receptors and atherogenesis regulators of gene expression in vascular cells [J]. CircRes, 2004,94(9):1168-1178.
[2]张慧灵,顾振纶,秦正红.PPARs与神经退行性疾病[J].中国药理学通报,2006,22(4)：397-402.
[3]Guan Y,ZhangY,BreyerMD.The Role of PPARs in the Transcriptional Control of Cellular Processes[J].Drug News Perspect,2002,15:147-154.
[4]Chinetti G,Fruchart JC,Staels B.Peroxisome proliferator-ativated receptors (PPARs):nuclear receptors at the crossroads between lipidmetabolism and inflammation[J].Inflamm Res,2000,49(10):497-505.
[5]Libby P.Inflammation in atherosclerosis[J].Nature,2002,420:868-874.
[6]Zambon A,Gervois P,Pauletto P,et al.Modulation of hepatic inflammatory risk markers of cardiovascular diseases by PPAR-alpha activators:clinical and experimental evidence[J].Arterioscler Thromb Vase Bio J 2006,26:977-986.
[7]Chinetti G,Griglio S,Antonucei M,et al.Activation of proliferactor activated receptors α and γ induces apoptosis of human monocyte derived macrophages [J].Biol Chem,1998,237(40):25575-25580.
[8]Tordjman K,Bernal-Mizrachi C,Zemany L,et al.PPAR alpha deficiency reduces insulin resistance and atherosclerosis in apoE-null mice[J].J Clin Invest,2001, 107:1025-1034.
[9]Mardones P,Pilon A,Bouly M,et al.Fibrates down-regulate hepatic scavenger receptor class B type I protein expression in mice[J].J Biol Chem,2003,278: 7884-7890.
[10]Devchand PR,Keller H,Peters JM,et al.The PPARa-leukotriene B4 pathway to inflammation control[J].Nature,1996,384:39-43.
[11]Delerive P,Bosscher KD,Besnard S,et al.Peroxisome proliferators-activated receptor-α negatively regulates the vascular inflammatory gene response by negative Cross-talk with transcription factors NF-κB and AP-1[J].J Biol Chem,1999,274:32-48.
[12]Delerive P,Martin-Nizard F,Chinetti G,et al. PPAR activators inhibit thrombin-induced endothelin-1 production in human vascular endothelial cells by inhibiting the AP-1 signalling pathway[J].Circ Res,1999,85:394-402.
[13]Marx N,Sukhova GK,Collins T,et al.PPARalpha agonists inhibit cytokine-induced vascular cell adhesion molecule-1 expression in human endothelial cells [J].Circulation,1999,99(24):3125-3131.
[14]陈丽红,杨光锐,管又飞.PPARα、PPARγ及其双激动剂与动脉粥样硬化[J].生理科学进展,2007,38(2)：153-155.
[15]Vosper H,Khoudoli G,Graham T,et al.Peroxisome proliferators activated receptor agonists, hyperlipidaemia and Atherosclerosis[J]. Pharmacol Ther,2002,95(1): 47-62.
[16]Gervois P,Torra I,Fruchart JC,et al.Regulation of lipid andlipoprotein metabolism by PPAR activator[J].Clin Chem Lab Med,2000,38(1):3-11.
[17]Xu XP,Meisel SR,Ong JM,et al.Oxidized low-density lipoprotein regulates matrix metalloproteinae-9 and its tissue inhibitor in human monocyte-derived macrophages[J].Circulation,1999,99(8):993-998.
[18]Eberhardt W,Akoolel S,Rebhan J,et al.Inhibition of cytokine-induced matrixmetalloproteinase 9 expression by peroxisome proliferator-activated receptor alpha agonists is in directand due to a NO-mediated reduction of mRNA stability[J]J BiolChem,2002,277(36):33518-33528.
[19]Ricote M,Li AC,Willson TM,et al.The peroxisome proliferator-activated receptor-γ is a negative regulator of macrophage activation [J]. Nature,1998, 391:79-82.
[20]Ishibashi M,Egashira K,Hiase K,et al.Anti-inflammatory and anti-arteriosclerotic effects of pioglitazone [J].Hypertension,2002,40(5):687-693.
[21]Chun SW, Kang BY,Kim SH,et al.Oxidized low density lipoprotein inhibits interleukin-12 production in lipopolysacchride-activated mouse macrophages viadirect interactions between PPARγ and NF-κB[J].J Biol Chem,2000, 276(32):681-687.
[22]Daynes RA,Jones DC.Emerging roles of PPARs in inflammation and immunity [J].Nat Rev Immuno J,2002,2(10):748-759.
[23]Yang XY,Wang LH,Chen T,et al.Activation of human T lymphocytes is inhibited by peroxisome proliferator2activated receptor γ (PPAR γ) agonists[J].J Biol Chem,2000,275(4):541-544.
[24]Bouhlel MA,Derudas B,Rigamonti E,et al.PPARgamma activationprimes human monocytes into alternative M2 macrophages with anti inflammatory properties[J].Cell Metab,2007,6(2):137-143.
[25]Nagy L,Tontonoz P,Alvarez JGA,et al.Oxidized LDL regulates macrophage gene exression through ligand activation of PPAR γ [J].Cell,1998,93:229-240.
[26]Tontonoz P,Nagy L,Alvarez JGA,et al.PPAR γ promotes moocyte/macrophage differentiation and uptake of oxidized LDL[J].Cell,1998,93:241-252.
[27]Argmann CA,Sawyez CG,McNeil CJ,et al.Activation of peroxisome proliferator-activated receptor gamma and retinoid X receptor results in net depletion of cellular cholesteryl esters in macrophages exposed to oxidized lipoproteins[J].Arterioscler Thromb Vasc Biol,2003,23(3):475-482.
[28]Francis GA,Fayard E,Picard F,et al.Nuclear receptors and the control of metabolism[J].Annu Rev Physiol,2003,65:261-311.
[29]Larsen TM,Toubro S,Astrup A.PPAR gamma agonists in the treatment of type Ⅱ diabetes:is increased fatness commensurate with long-term efficacy[J].Int J Obes Relat Metab Disord,2003,27(2):147-161.
[30]Shibasaki M,Takahashi K,Itou T,et al.A PPAR agonist improves TNF-a induced insulin resistance of adipose tissue in mice[J].Biochem Biophy Res Commu,2003,309(2):419-424.
[31]Meredith D,Panchatcharam M.Dominant-negative loss of PPAR-gamma function enhances smooth muscle cell proliferation,migration, and vascular remodeling[J].Arterioscler Thromb Vase Bio J,2009,29(4):465-471.
[32]SooL,Cheng JJ,Min K,et al.PPARgamma gene transfer sustains apoptosis, inhibits vascular smooth muscle cell proliferation, and reduces neointima formation after balloon injury in rats[J].Arterioscler Thromb Vase Bio J.2006,26(4):808-813.
[33]Goetze S,Xi XP,Kawano H,et al.PPAR-ligands inhibit migration mediated by multiple chemoattractants in vascular smooth muscle cells[J]. J Cardiovasc Pharmacol.1999,33:798-806.
[34]Marx N,Schonbeck U,Lazar MA,et al.Peroxisome proliferator-activated receptor activators inhibit gene expression and migration in human vascular smooth muscle cells[J].Circ Res.1998,83:1097-1103.
[35]Forman BM,Tontonoz P,Chen J,et al.15-Deoxy-delta-12,14-prostaglandin J2 is a ligand for the adipocyte determination factor PPAR gamma [J]. Cell,1995, 83:803-812.
[36]Tontonoz P,Nagy L,Alvarez JGA,et al.PPAR γ promotes moocyte/macrophage differentiation and uptake of oxidized LDL[J].Cell,1998,93:241-252.
[37]Krey G,Braissant O,L'Horset F,et al.Fatty acids, eicosanoids, and hypolipidemic agents identified as ligands of peroxisome proliferator-activated receptors by co-activator-dependent receptor ligand assay [J].Mol Endcrinol,1997,11:779-791.
[38]Robins SJ,Collins D,Wittes JT,et al.Relation of gemfibrozil8 treatment and lipid levels with major coronary events[J].J Am Med Assoc,2001,285:1585-1591.
[39]Grossman SL,Lessem J.Mechanisms and clinical effects of thiazolidinediones [J]. Exp Opin Invest Drugs,1997,6:1025-40.
[40]Lehmann JM,Oliver BB,Ringold GM,et al.Peroxisome proliferator-activated receptors α and β are activated by indomethacin and other non-sterooidal anti-inflammatoru drugs[J].J Biol Chem,1997,79:81-94.
[41]Buckle DR,Cantello,BCC,Cawthorne,MA,et al.Non thiazolidine-dione antihyperglycaemic agents:a-Heteroatom substitutedβ-phenylpropanoic acids[J]. Bioorganic and Medicinal Chem Lett.1996,6(17):2121-2130.
[42]Brook DA,Etgen GJ,Rito CJ,et al.Design and synthesis of 2-methyl-2-{4-[2-(5-methyl-2-aryloxazol-4-yl) ethoxy]phenoxy}-pro-pionic acids:A new class of dual PPAR α/γ agonists[J].J Med Chem,2001,44:2061-2064.
[43]Ushiroda K,Maruta K,Takazawa T,et al.Synthesis and Pharmaco-logical Evaluation of Novel Benzoylazole-Based PPARα/γ Activators[J].Bioorganic & Medicinal Chemistry Letters,2011,doi:10.1016/j.bmcl.2011.02.032.
[44]DAIS.Effect of fenofibrate on progression of coronary-artery disease in type 2 diabetes:the DiabetesAtherosclerosis Intervention Study,a randomised study[J].Lancet,2001,357(9260):905-910.
[45]Staels B,Koening W,Habib A,et al. Activation of human aortic smooth muscle cell is inhibited by PPARα but not by PPARγ activators[J]. Nature,1998, 393:790.
[46]Madej A,Okopien B,Kowalski J,et al.Effects of fenofibrate on plasma cytokine concentrations in patients with atherosclerosis and hyperlipoproteinemia Ⅱ b[J].Int J Pharmacol Thera,1998,36:345-349.
[47]Ferreira AV,Parreira GG,Green A,etal.Effects of fenofibrate on lipidmetabolism in adipose tissue of rats[J].Metabolism,2006,55(6):731-5.
[48]Delerive P,Gervois P,Fruchart JC,et al.Induction of κ IB α expression as a mechanism contributing to the anti2inflammatory activities of PPAR a activators[J].J Biol Chem,2000,27(36):703-707.
[49]周晓惠,王佑民,王文平等.吡格列酮和非诺贝特对高脂饲养大鼠脂联素与胰岛素抵抗的影响[J].安徽医科大学学报,2008,43(4)：418-421.
[50]Oki K,Koide J,Nakanishi S,et al.Fenofibrate increases high molecular weight adiponectin in subjects with hypertriglyceridemi[J].Endocr J,2007,54(3):431-5.
[51]Mangan S,Clancy P,Golledge J.Modulation of endothelial cell thrombomodulin by PPAR ligands-Variation according to environment [J].Thromb Res,2007,13[Epub ahead ofprint].
[52]Sidhu JS,Kaposzta Z,MarkusHS,et al.Effect of rosiglitazone on common carotid intima-media thickness progression in coronary artery disease patientswithout diabetesmellitus[J].Arteriosclerosis Thrombosis & Vascular Biology,2004,24(5): 930-934.
[53]Kang QH,Chen AP,Jawahar.S1896 curcumin inhibits Ox-LDL-activated hepatic stellate cells in vitro by suppressing gene expression of lectin-like oxidized-LDL receptor via activation of peroxisome proliferator-activated receptor-gamma [J].Gastroenterology,2008,134 (4):A-779.
[54]Spanheimer R,Betteridge J,Tan MH,et al.Long-term lipid effects of pioglitazone by baseline anti-hyperglycemia medication therapy and statin use from the PROactive experience (PROactive 14)[J].The American Journal of Cardiology, 2009,104(2):234-239.
[55]Davidson M,Meyer PM,Haffner S,et al.Increased high-density lipoprotein cholesterol predicts the pioglitazone-mediated reduetionof carotid intima-media thickness progression in patientswith type 2 diabete smellitus[J]. Circulation, 2008,117:2123-2130.
[56]楚罗香,姜德谦,刘照云.吡格列酮对人脐静脉内皮细胞CD40/CD40L表达的影响[J].中国药物与临床,2006,6(1)：48-51.
[57]Horio T,Suzuki M,Takamisawa I,et al.Pioglitazone-induced insulin sensitization improves vascular endothelial function in nondiabetic patients with essential hypertension[J].Am J Hypertens,2005,18:1626-1630.
[58]Benomar Y,Roy AF,Aubourg A,et al.Cross down-regulation ofLeptin and insulin receptor expression and signalling in a human neuronal cell line [J]. Biochem, 2005,388:929-939.
[59]Ruiz E,Redondo S,Gordillo-Moscoso A,et al.Pioglitazone induces apoptosis in human vascular smoothmuscle cells from diabetic patients involving the transforming growthfactor-beta/activin receptor-like inase-4/5/7/Smad2 signaling pathway [J].Pharmacol Exp Ther,2007,321(2):431-438.
[60]袁晓晨,刘乃丰,严金川等.过氧化物酶体增殖物激活受体γ对糖基化终产物诱导大鼠血管平滑肌细胞增殖的作用[J].中华心血管病杂志,2005,33(10)：940-944.
[61]Gensch C,CleverY,WernerC,et al.The PPAR-yagonistpioglitazone increases neoangiogenesis and prevents apoptosis of endothelial progenitor cells[J] Atherosclerosis,2007,192:67-74.
[62]Werner C,Kamani CH,Gensh C,et al.The peroxisome proliferator-activated receptor-gamma agonist pioglitazone increases number and function of endothelial progenitor cells in patients with coronary artery disease and normal glucose tolerance [J]. Diabetes,2007,56 (10):2609-2615.
[63]骆雷鸣,朱启伟.苯扎贝特对高甘油三酯血症患者脂代谢及糖代谢的影响[J].中国实用内科杂志,2009,29(4)：1-4.
[64]Zahradka P,Wright B,Fuerst M,et al.Peroxisome proliferators-activated receptor alpha and gamma ligands differentially affect smooth muscle cell proliferation and migration[J].J PharmacolExp Ther,2006,317:651-659.
[65]Li AC, Binder CJ,Gutierrez A,et al.Differential inhibition of macrophage foam-cell formation and atherosclerosis in mice by PPARalpha,beta/delta,and gamma[J].J Clin Invest,2004,114:1564-1576.
[66]Reifel-Miller A,Otto K,Hawkins E,et al.A peroxisome proliferators-activated receptor dual agonist with a unique in vitro profile and potent glucose and lipid effects in rodent models of type 2 diabetes and dyslipidemia[J].Molecular Endocrinology,2005.19 (6):1593-1605.
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