过氧化脂质体增殖激活受体与心肾疾病

过氧化脂质体增殖激活受体 (PPARs)参与了许多慢性疾病的形成 ,PPARs的活性能被特异性配体所调控。本文就PPARs进行简述 ,同时主要就PPARs与动脉粥样硬化及肾脏疾病的研究进展做一综述。     

过氧化物酶体增殖活化受体α与动脉粥样硬化的关系及其研究进展

过氧化物酶体增殖活化受体α(PPARα)作为核受体超家族的一员,不仅参与调节脂类和葡萄糖的代谢,而且参与了血管生物学及炎症反应,PPARα通过调节炎性细胞因子及表面黏附分子的表达、抑制巨噬细胞活化、促进胆固醇的逆转运、抑制血管平滑肌细胞增殖和迁移等而达到抗动脉粥样硬化的作用,但也有一少部分试验得出了相反的结论,本文综述了PPARα与动脉粥样硬化的关系及其进展。     

过氧化物酶体增殖物激活受体γ与肝癌

过氧化物酶体增殖物激活受体(PPAR)γ是核激素受体超家族成员,在肝癌组织及细胞株中均有表达.PPARγ可调节细胞因子、炎症介质的产生,参与氧自由基生成和氧化应激,调节细胞外基质平衡,调控细胞周期及凋亡、增殖活性,在肝癌的生物学行为中发挥重要作用.     

过氧化物酶体增殖物活化受体与非酒精性脂肪性肝病

非酒精性脂肪性肝病(NAFLD)的发病率正在逐年升高,肝脏脂肪沉积是NAFLD的临床病理特征和诊断的金标准.过氧化物酶体增殖物活化受体(PPARs)是配体激活的核受体,在脂代谢、糖代谢和炎性反应中起关键作用,其可作为治疗NAFLD的靶点.PPARs激动剂可减少肝内脂肪沉积,从而逆转NALFD的发展进程,但因其尚存在较多不良反应,所以对PPARs与NAFLD的机制需要进一步研究,从而为PPARs治疗NAFLD提供更有力的证据.     

替米沙坦对肝纤维化大鼠肝组织病理学变化的影响

目的观察替米沙坦对四氯化碳（CCl4）诱导的大鼠实验性肝纤维化模型肝组织病理学变化的影响。方法 SD大鼠40只被随机分成正常对照组（12只）、模型组（12只）和替米沙坦防治组（16只）。在制备大鼠肝纤维化动物模型成功后,取肝、脾,常规进行组织病理学检查。结果模型组大鼠平均肝指数为4.85±0.42（P〈0.05）,正常对照组为2.92±0.41,而药物干预组为3.09±0.36;模型组大鼠肝炎症活动度平均计分为18.6±2.1（P〈0.05）,正常对照组为0.0±0.0,替米沙坦干预组为8.6±1.9;模型组大鼠肝纤维化计分平均为14.5±1.6,正常对照组为0.33±0.49,替米沙坦干预组为7.7±1.7（P〈0.01）。结论替米沙坦可改善实验性纤维化大鼠肝组织病理学损伤。     

Peroxisome proliferator-activated receptor-delta agonist ameliorated inflammasome activation in nonalcoholic fatty liver disease

AIM: To evaluate the inflammasome activation and the effect of peroxisome proliferator-activated receptors (PPAR)-δ agonist treatment in nonalcoholic fatty liver disease (NAFLD) models.METHODS: Male C57BL/6J mice were classified according to control or high fat diet (HFD) with or without PPAR-δ agonist (GW) over period of 12 wk [control, HFD, HFD + lipopolysaccharide (LPS), HFD + LPS + GW group]. HepG2 cells were exposed to palmitic acid (PA) and/or LPS in the absence or presence of GW.RESULTS: HFD caused glucose intolerance and hepatic steatosis. In mice fed an HFD with LPS, caspase-1 and interleukin (IL)-1β in the liver were significantly increased. Treatment with GW ameliorated the steatosis and inhibited overexpression of pro-inflammatory cytokines. In HepG2 cells, PA and LPS treatment markedly increased mRNA of several nucleotide-binding and oligomerization domain-like receptor family members (NLRP3, NLRP6, and NLRP10), caspase-1 and IL-1β. PA and LPS also exaggerated reactive oxygen species production. All of the above effects of PA and LPS were reduced by GW. GW also enhanced the phosphorylation of AMPK-α.CONCLUSION: PPAR-δ agonist reduces fatty acid-induced inflammation and steatosis by suppressing inflammasome activation. Targeting the inflammasome by the PPAR-δ agonist may have therapeutic implication for NAFLD.     

过氧化物酶体增殖物激活受体辅调节因子与肾脏损伤的关系

过氧化物酶体增殖物激活受体(PPARs)作为一类核转录因子,能与其特异性配体结合,进而在转录水平上调节多种基因的表达。近年来研究发现,PPARs的辅调节因子,包括辅激活因子和辅抑制因子,能够通过不同的机制促进或抑制PPARs的转录活性,调节其目的基因的表达。并且还是很多细胞内信号通路和翻译后修饰作用的对象,在肾脏疾病的进展中发挥重要重要。选择不同的辅调节因子的激活剂或抑制剂来调节相关基因的转录活性,将会成为治疗一些肾脏疾病如肾小球硬化、肾小球肾炎、糖尿病肾病及肾小管间质疾病的新的治疗手段和方法。     

Peroxisome proliferator-activated receptor delta and cardiovascular disease

Recent reports have shown that peroxisome proliferator-activated receptor delta (PPARD) plays an important role in different vascular processes suggesting that PPARD is a significant modulator of cardiovascular disease. This review will focus on PPARD in relation to cardiovascular risk factors based on cell, animal and human data. Mouse studies suggest that Ppard is an important metabolic modulator that may have implications for cardiovascular disease (CVD). Specific human PPARD gene variants show no clear association with CVD but interactions between variants and lifestyle factors might influence disease risk. During recent years, development of specific and potent PPARD agonists has also made it possible to study the effects of PPARD activation in humans. PPARD agonists seem to exert beneficial effects on dyslipidemia and insulin-resistant syndromes but safety issues have been raised due to the role that PPARD plays in cell proliferation. Thus, large long term outcome as well as detailed safety and tolerability studies are needed to evaluate whether PPARD agonists could be used to treat CVD in humans.     

过氧化物酶体增殖物激活受体γ激动剂在终末期肾脏病中的研究进展

过氧化物酶体增殖物激活受体γ(PPAR-γ)是一种细胞核受体,除了能够调节机体糖脂代谢外,在抗炎、抗纤维化、调节免疫及抗动脉粥样硬化等方面也发挥着重要作用。终末期肾脏病(ESRD)患者由于疾病本身和肾脏替代治疗的介入常存在胰岛素抵抗和微炎症状态,心血管疾病的发病率和死亡率显著高于普通人群。新近关于PPAR-γ激动剂应用于ESRD的研究结果提示PPAR-γ激动剂能够改善ESRD患者上述病理生理。本文就这方面的研究进展以及目前有关热点问题进行综述。     

我国高血压专病门诊患者血压控制及糖代谢调查现状分析

目的 探讨高血压专病门诊就诊的高血压患者血压控制率、血糖现状和危险因素分布.方法 在全国127家医院的高血压专病门诊采用横断面调查的方法,对门诊顺序入组的32 004例高血压患者开展病史询问、血压测量及生化血检查,并进行统计学检验分析.结果 (1)血压达标率(＜ 140/90 mm Hg)(1 mm Hg =0.133 kPa):全部人群达标率为26.8％.冠心病、糖尿病、肾病和卒中的达标率分别为27.7％、30.0％、25.4％和21.3％.(2)接受调查的全部受试者的血压均值为(151 ±13)/(92±10)mm Hg,未服用降压药物3424例(10.7％).药物治疗者28 580例(89.3％).单药治疗19 818例(69.3％),联合用药治疗8762例(30.7％),使用最多的药物是肾素血管紧张素系统抑制剂,其次为钙通道阻滞剂.(3)高血压患者中有70.3％存在糖代谢异常,仍有20.2％未服降糖药物,这组患者糖化血红蛋白为7.84％.(4)患者的危险分层:低、中危占16.0％,高危和极高危分别占48.0％和36.0％,其中有50.0％患者存在不同程度与靶器官损害,49.0％患者并存其他临床疾病.结论 高血压患者中联合治疗的比例较低并是血压控制不良的原因之一,血压控制率不足30％;高血压患者中糖代谢异常普遍存在,有更多靶器官损害及临床疾病,有效的血压管理势在必行.     

缬沙坦对高血压患者脉压及氧化应激反应的影响

目的探讨氧化应激反应变化在血管紧张素Ⅱ1型受体阻断剂（ARB）改善高血压患者脉作中的作用。方法连续65例门诊就诊的无并发症、半年内未用ARB及血管紧张素转换酶抑制剂类药的高血压患者随机分成两组：对照组32例,常规降压药物治疗;缬沙坦组33例,常规降压药物＋缬沙坦80mg／d治疗。分组治疗12个月。以动态血压观察患者治疗前、后血压变化,并以逆转录聚合链式反应（RT-PCR）方法测定血白细胞p22^phox mRNA的表达。结果治疗前两组患者性别、年龄、基础血压（包括收缩压、舒张压、脉压）及外周血白细胞p220^phox mRNA表达差异均无统计学意义（均P〉0．05）。治疗后两组患者收缩压、舒张压及脉压均较治疗前明显降低,差异有统计学意义（P〈0．05）。治疗后缬沙坦组收缩压及舒张压与对照组比较差异无统计学意义[其中收缩压（134．32±14．52）mmHg比（137．15±12．10）mmHg,舒张压（82．63±13．96）mmHg比（77．35±11．38）mmHg,P〉0．05],但脉压下降程度明显大于对照组（27．39％比11．91％,P〈0．05）。治疗后两组患者白细胞p22^phox mRNA表达均较治疗前降低,其中对照组白细胞p22^phox mRNA表达较治疗前减少18％．但差异无统计学意义（P=O．0732）,缬沙坦组白细胞p22^phox mRNA表达较治疗前减少76％（P〈0．01）。结论缬沙坦治疗12个月,能降低高血压患者的脉压,抑制高血压患者外周血白细胞NAD（P）H氧化酶亚基p22^phox mRNA的表达。缬沙坦改善动脉弹性、抗动脉硬化的效应可能归因于其具有的抗氧化作用。     

Peroxisome proliferator-activated receptor γ agonist reduces the severity of post-ERCP pancreatitis in rats

AIM: To determine the effects of prophylactic peroxi-some proliferator-activated receptor (PPARgamma) agonist administration in an experimental model of post-endoscopic retrograde cholangiopancreatography (post-ERCP) acute pancreatitis. METHODS: Post-ERCP pancreatitis was induced in male Wistar rats by infusion of contrast medium into the pancreatic duct. In additional group, rosiglitazone, a PPARgamma agonist, was administered 1 h before infusion of contrast medium. Plasma and pancreas samples were obtained 6 h after the infusion. RESULTS: Infusion of contrast medium into the pan-creatic duct resulted in an inflammatory process characterized by increased lipase levels in plasma, and edema and myeloperoxidase activity (MPO) in pancreas. This result correlated with the activation of nuclear factor kappaB (NFkappaB) and the inducible NO synthase (iNOS) expression in pancreatic cells. Rosiglitazone reduced the increase in lipase and the level of edema and the increase in myeloperoxidase as well as the activation of NFkappaB and iNOS expression. CONCLUSION: A single oral dose of rosiglitazone, given 1 h before post-ERCP pancreatitis induction is effective in reducing the severity of the subsequent inflammatory process. The protective effect of rosiglitazone was associated with NFkappaB inhibition and the blockage of leukocyte infiltration in pancreas.     

替米沙坦保护胰岛β细胞功能的研究进展

替米沙坦作为血管紧张素Ⅱ受体拮抗剂(ARBs),兼具有部分过氧化物酶体增殖物活化受体γ (PPARγ)激动剂的作用.研究提示,除降压作用外,其还有一定的改善胰岛素抵抗的作用.近年发现,替米沙坦也能够保护胰岛β细胞功能.其机制主要与阻断肾素-血管紧张素系统(RAS)和激活PPARγ有关.     

Comparative analysis of the in vivo angiogenic properties of stable prostacyclin analogs: a possible role for peroxisome proliferator-activated receptors

OBJECTIVE: Until recently, prostacyclin (PGI2) biological activities were thought to be exclusively mediated by cell surface receptors named IP. Recent studies have instead identified a novel pathway of PGI2 signaling, occurring through activation of peroxisome proliferator-activated receptors (PPARs) located in the nucleus. The availability of stable PGI2 analogs with different affinity for IP receptors and PPARs provides the possibility to test the importance and function of this dual pathway in vitro and in vivo. In this study, the in vivo angiogenic properties of different PGI2 analogs and the potential relationship between PPAR-mediated pathways, vascular endothelial growth factor (VEGF), and angiogenesis were investigated. METHODS AND RESULTS: By using the murine corneal model of angiogenesis, we found that PGI2 analogs able to act on nuclear PPARs, such as iloprost and carbaprostacyclin (cPGI), induce angiogenesis in vivo. In contrast, cicaprost, a PGI2 analog that only acts on IP receptors, has no in vivo angiogenic activity. Interestingly, angiogenesis induced by iloprost and cPGI does not differ in extent and morphology from that induced by VEGF and is associated with local increment of VEGF mRNA expression and protein levels. Finally, iloprost-induced angiogenesis is significantly decreased by systemic inhibition of VEGF activity, obtained by gene transfer of a soluble form of the VEGF receptor Flt-1. CONCLUSIONS: These data demonstrate that stable PGI2 analogs may have angiogenic properties in vivo, depending on their ability to act on PPARs. The resulting angiogenic process appears to be mediated by VEGF. These findings indicate that important physiological activities in the cardiovascular system, such as angiogenesis and VEGF induction, may be modulated by PGI2 through specific activation of the PPAR signaling pathway in vivo, with potentially important fundamental and clinical implications.     

Peroxisome proliferator-activated receptor α, a potential therapeutic target for alcoholic liver disease

Alcoholic liver injury represents a progressive process with a range of consequences including hepatic steatosis, steatohepatitis, liver fibrosis, cirrhosis, and hepatocellular carcinoma. Targeting key molecular regulators involved in the development of alcoholic liver injury may be of great value in the prevention of liver injury. Peroxisome proliferator-activated receptor α (PPARα) plays a pivotal role in modulation of hepatic lipid metabolism, oxidative stress, inflammatory response and fibrogenesis. As such, PPARα may be a potential therapeutic target for the treatment of alcoholic liver disease.     

过氧化物酶体增殖物激活受体γ激动剂对大鼠胰腺腺泡细胞信号传导途径的影响

目的 了解经雨蛙肽处理的胰腺腺泡细胞AR42J中过氧化物酶体增殖因子活化受体γ(PPARγ)与核因子(NF)-κB活性间的关系.方法 将胰腺腺泡AR42J细胞分为对照组(常规培养)、吡咯列酮组(40 μmol/L吡咯列酮)、吡咯列酮+雨蛙肽组(40 μmol/L吡咯列酮+10~(-8) mol/L雨蛙肽)、雨蛙肽组(40 μmol/L二甲基哑砜+10~(-8)mol/L雨蛙肽)和吡咯列酮+GW9662+雨蛙肽组(40 μmol/L吡咯列酮+5 μmol/L GW9662+10~(-8)mol/L雨蛙肽),各组培养30 min后检测PPARγ和NF-κB活性.Western印迹法检测NF-κB、PPARγ蛋白和磷酸化NF-κB抑制物(IκB)α抗体、IκB激酶(IKK)β和IκBα的表达差异、IKKβ活性和IκBα磷酸化的变化.免疫荧光法和Western印迹法检测NF-κB(p65和p50)的核移位.免疫沉淀法检测IκBα与NF-κB的变化.结果 吡咯列酮不仅抑制IKKβ活性(吡咯列酮+雨蛙肽组:雨蛙肽组为1.6;3.7)及IκBα的磷酸化(吡咯列酮+雨蚌肽组:雨蛙肽组为0.9:1.5),还能加强IκBα与NF-κB的结合(吡咯列酮+雨蛙肽组:雨蛙肽组为0.8:0.3),抑制NF-κB的核移位及NF-κB的转录活性(P<0.01),而PPARγ拮抗剂GW9662则逆转了吡咯列酮对NF-κB活性的抑制作用(P<0.05).结论 在雨蛙肽处理的AR42J细胞中PPARγ通过干扰NF-κB的活化产生抗炎作用.     

Beneficial effect of combination therapy with antihypertensive drugs in patients with hypertension

BACKGROUND: Cardiac hypertrophy and failure are major complications of hypertension. OBJECTIVES: The beneficial effect of treatment with antihypertensive drugs on serum levels of brain natriuretic peptide (BNP) was examined in patients with essential hypertension. METHODS: Antihypertensive drugs were administered to 88 hypertensive patients (44 diabetic and 44 nondiabetic) whose systolic blood pressure was greater than 140 mmHg and/or diastolic blood pressure was greater than 90 mmHg. Other antihypertensive drugs were added every two months until the blood pressure fell below 130/85 mmHg. Candesartan, benidipine, bisoprolol or celiprolol, and bunazosin were administered in this order. RESULTS: The mean systolic blood pressure was reduced from 163.7+/-11.6 mmHg to 121.8+/-7.5 mmHg after 12 months in patients with diabetes and from 167.6+/-12.3 mmHg to 122.8+/-7.5 mmHg in patients without diabetes. The mean diastolic blood pressure was also significantly reduced in patients with and without diabetes. Serum BNP levels were reduced from 52.2+/-38.8 pg/mL to 38.8+/-30.9 pg/mL in patients with diabetes and from 47.1+/-34.2 pg/mL to 35.8+/-22.5 pg/mL in patients without diabetes. In patients older than 70 years of age, serum BNP levels were reduced from 56.3+/-39.3 pg/mL to 40.2+/-23.0 pg/mL in those with diabetes and from 54.6+/-32.9 pg/mL to 38.0+/-16.0 pg/mL in those without diabetes. CONCLUSIONS: These results indicate that combination therapy with antihypertensive drugs is usually necessary to reduce blood pressure to below 130/85 mmHg and to improve serum BNP levels.