PPAR-γ配体对氧化应激诱导大鼠心肌炎症反应的抑制效应及相关分子机制的研究
|
摘要
目的:第一部分:采用氧化剂H_2O_2模拟氧自由基刺激大鼠心肌细胞,建立氧化应激诱导心肌细胞炎症反应的损伤模型。以体外原代培养的新生大鼠心室肌细胞为模型,从细胞生物学方面观察H_2O_2对心肌细胞的损伤效应。第二部分:在第一部分的基础上,探讨过氧化物酶增殖体活化受体-γ(PPAR-γ)配体在调节氧化应激诱导心肌炎症反应中的作用及可能的细胞保护机制。
方法:第一部分:用机械解离法和酶消化法分离培养新生大鼠心室肌细胞,采用差速贴壁分离技术和化学药物抑制法进行纯化。倒置相差显微镜下动态观察细胞形态,台盼蓝染色法测定细胞存活率,并用免疫荧光细胞化学技术鉴定心肌细胞纯度。MTT法检测不同浓度H_2O_2对新生大鼠心肌细胞活力的影响。采用缩时录像机8050对培养的心肌细胞动态进行录像,采集搏动图像,观察搏动情况并计数搏动频率。第二部分:第一部分的基础上,观察H_2O_2在不影响心肌细胞活性的作用浓度下(100μmol/L)诱导细胞分泌炎症介质的效应。采用RT-PCR检测目标炎性因子TNF-α与LIX mRNA水平的表达;ELISA检测细胞培养上清液中TNF-α蛋白含量;Western Blot检测胞浆中LIX和IκBα表达水平。观察PPAR-γ的天然配体15d-PGJ_2与合成配体吡格列酮对TNF-α与LIX表达的影响。利用电泳迁移率变动分析(EMSA)检测H_2O_2对核转录因子NF-κB的效应;Western Blot检测H_2O_2处理组胞浆中IκBα蛋白水平,以及PPAR-γ配体对H_2O_2处理后胞浆中IκBα蛋白表达的影响。同时采用EMSA技术检测15d-PGJ_2与吡格列酮对H_2O_2诱导NF-κB活化的影响;15d-PGJ_2和吡格列酮以及H_2O_2对心肌细胞内热休克转录因子HSF1 DNA结合活性的影响以及与NF-κB信号通路的关系。
结果:第一部分:(1)成功地分离培养原代新生大鼠心室肌细胞,细胞存活率95%以上;差速贴壁分离后,倒置显微镜下观察贴壁后心肌细胞呈梭形、菱形或多角形。8h后即可观察到部分心肌细胞自发性搏动,24h后心肌细胞已全部贴壁,90%以上搏动,48h心肌细胞聚集成簇,细胞搏动趋向同步化。免疫荧光染色鉴定心肌细胞来源及细胞纯度达95%以上,并可见心肌特异性横纹结构。(2)正常培养条件下,在两周不同培养时间内心肌细胞的搏动频率无统计学差异,表明在观察期限内心肌细胞活力保持不变。(3)不同浓度H_2O_2作用心肌细胞48h后,MTT检测的结果显示,10μmol/L和50μmol/L的H_2O_2对心肌细胞活性无影响。100μmol/L的H_2O_2轻微抑制心肌细胞的活性,但无显著性差异(P＞0.05)。200μmol/L的H_2O_2明显抑制心肌细胞活性,具有统计学意义(P＜0.05)。(4)通过采集的搏动图像,观察并记录各处理组心肌细胞的搏动频率后统计结果显示,100μmol/LH_2O_2作用后48h内,对心肌细胞搏动频率无明显影响(P＞0.05),200μmol/L的H_2O_2作用4h后,即显著抑制心肌细胞的搏动频率(P＜0.05),并随时间的延长其抑制效应明显增强(P＜0.01)。第二部分:(1)100μmol/L H_2O_2作用心肌细胞30min后,炎症介质TNF-α和LIX表达开始升高,4h达到峰值后逐渐下降。NF-κB特异性抑制剂SN50明显抑制H_2O_2诱导TNF-α和LIX的生成(P＜0.05)。(2)100μmol/L H_2O_2呈时间依赖性地激活NF-κB,4h时活化达到高峰值(P＜0.01),至8h时逐渐降低(P＜0.05)。H_2O_2升高了胞浆内IκBα磷酸化水平并促进其降解(P＜0.05)。(3)15d-PGJ_2与吡格列酮呈浓度依赖性地抑制H_2O_2诱导的TNF-α与LIXmRNA及蛋白水平的表达(P＜0.05)。(4)5μmol/L 15d-PGJ_2或10μmol/L吡格列酮预处理30min后,二者均未明显抑制H_2O_2诱导的IκBα降解,而延长处理时间至3h时,可以显著升高H_2O_2处理后胞浆内IκBα的蛋白水平(P＜0.05)。(5)PPAR-γ配体以浓度依赖性的方式抑制NF-κB的转录活性,而在相同浓度(10μmol/L)时,15d-PGJ_2的抑制作用强于吡格列酮。同时,PPAR-γ特异性抑制剂GW9662可明显减弱吡格列酮对NF-κB的抑制作用,但未影响15d-PGJ_2对NF-κB的作用。(6)5μmol/L 15d-PGJ_2处理3h时HSF1与其反应元件的结合能力显著增强(P＜0.05),而此时吡格列酮与H_2O_2处理后的心肌细胞中HSF1的活性未见明显改变。(7)15d-PGJ_2处理心肌细胞3h后,激活HSF1的同时可显著抑制H_2O_2诱导的IκBα降解,而在其预处理30min内,HSF1未被明显激活的同时,亦未能有效抑制H_2O_2诱导的IκBα降解。(8)15d-PGJ_2呈浓度依赖性的激活HSF1的同时抑制H_2O_2诱导的NF-κB活化。而且,15d-PGJ_2诱导HSF1活化以及对NF-κB的抑制效应均未被GW9662阻断。
结论:(1)NF-κB信号途径介导了氧化应激诱导大鼠心肌细胞分泌炎性因子TNF-α与LIX。(2)PPAR-γ配体以浓度依赖性的方式抑制心肌细胞分泌TNF-α与LIX。(3)15d-PGJ_2与吡格列酮抑制心肌细胞中NF-κB的转录活性,进而抑制其介导的炎性因子的表达。(4)15d-PGJ_2能以PPAR-γ非依赖性方式提高细胞内热休克反应,抑制氧化应激诱导的炎症反应,在转录水平抑制炎性因子的表达。
Objectives Part one:Hydrogen peroxide(H_2O_2) is a useful tool for studying the inflammatory response induced by reactive oxygen species(ROS) in myocardium.The current study aimed at investigating the properties of primary rat cardiac ventricular myocytes using cell biology technology to record their spontaneous pulsation under time-lapse video microscopy,and inspecting the role of H_2O_2 in cultured cardiomyocytes. Part two:On the basis of part one,this part was designed to evaluate the effects of two distinct ligands of PPAR-γin regulating the inflammatory response induced by oxidative stress,and to examine the potential molecular mechanisms of their cardioprotective effects.
Methods Part one:(1) Neonatal rat cardiomyocytes were isolated with mechanical dissection and enzyme digestion,then purified by means of differential attachment technique and chemical drug inhibition.Morphological changes of cardiomyocytes were observed dynamically with phase-contrast microscopy.The ratio of survival cells was identified by trypan blue staining.The purity of cardiomyocytes was evaluated by immunofluorescence staining with antibody to cardiacα-sarcomeric actin.MTT method was carried out to assay the cell viability when treated with different concentration of H_2O_2.The rhythmic pulsation of the cardiomyocytes was followed microscopically using a time-lapse recorder 8050 before and at various time points during treatment.To count the beating rate,the culture dishes were maintained on the microscope bench.Part two: On the basis of part one,we investigated the effects of a certain concentration of H_2O_2 (100μmol/L) on expression of the proinflammatory cytokine in cardiac myocytes.The expression of TNF-αand LIX mRNA were detected by RT-PCR;the levels of TNF-αin the supematants were measured with commercially available enzyme-linked immunosorbent assay kit;Wwestern blot analysis was performed to detect the LIX and IκBαprotein in the cytoplasm.To investigate whether two chemically unrelated PPAR-γligands,15d-PGJ_2 and pioglitazone could regulate the expression of TNF-αand LIX,the gel electrophoresis mobility shift assay(EMSA) was used to detect the transcriptor factor NF-κB activity under the challenge of H_2O_2 by cardiomyocytes;Western blot analysis was used to detect the effects of 15d-PGJ_2 and pioglitazone on H_2O_2-induced IκBαdegradation;EMSA was performed to determine the effects of PPAR-γligands on the induction of NF-κB DNA binding activity in response to H_2O_2;the effect of 15d-PGJ_2 and pioglitazone or 100μmol/L H_2O_2 on the DNA binding of HSF1,and the relationship between NF-κB and HSF1 signaling pathway were also determined by EMSA.
Results Part one:(1) Primary cultures of neonatal rat cardiac myocytes were prepared from ventricles of Wistar rats.The ratio of survival cells was above 95%. Cardiomyocytes were isolated and purified by means of differential attachment technique. Morphological changes of cardiomyocytes were observed dynamically with phase-contrast microscopy,and the cell shape changed from circles to polygons or fusiform shape after attach along the flask.About 8 hours after plantation,partly cardiomyocytes began to beat spontaneously;after 24 hours all cardiomyocytes had attached and above 90%of them beated.Cardiomyocytes got together and beat synchronously in clusters after 48 hours.The purity of cardiomyocytes was above 95% and cross striation could be observed clearly.(2) Under normal conditions,the beating rate of the cells is no statistical difference at various time points within two weeks.(3) Incubation of cardiomyocytes with various concentrations of H_2O_2 for 48h,MTT analysis showed that there is no decrease in cell viability at concentrations of 10 and 50μmol/L;however,cardiomyocyte viability decreased slightly but not significant at a concentration of 100μmol/L(P＞0.05);200μmol/L H_2O_2 inhibited cell viability significantly(P＜0.05).(4) We recorded the action state of the selected cells using a time-lapse recorder 8050,and analyzed the data.The results indicated that 100μmol/L H_2O_2 has no effect on the beating rate of cell within 48h.After treatment cells with 200μmol/L H_2O_2,the beating rate of cell declined rapidly within 4 hours(P＜0.05),and decreased significantly in a time-dependent manner(P＜0.01)。
Part two:(1)The levels of TNF-αand LIX mRNA were induced within 30 minutes after stimulation with 100μmol/L H_2O_2,remained elevated for 4 hours,and decreased thereafter.The NF-κB-blocking peptide SN50 peptide could inhibit H_2O_2-inducd TNF-αand LIX mRNA expression.(2) Stimulation of cells with H_2O_2(100μmol/L) led to an increase in NF-κB binding activity reaching a plateau at 4 hours and at this time,the amount of IκBαprotein was notably reduced.(3) Both 15d-PGJ_2 and pioglitazone markedly decreased H_2O_2-induced TNF-αand LIX(mRNA and protein) expression in a concentration-dependent manner.(4) Myocytes were pretreated either 30 minutes or 3 hours with 5μmol/L 15d-PGJ_2 or 10μmol/L pioglitazone.Neither 15d-PGJ_2 nor pioglitazone could inhibit H_2O_2-induced IκBαdegradation after a 30-min preincubation, while H_2O_2-induced IκBαdegradation was attenuated if cells were preincubated for 3 hours with 15d-PGJ_2 or pioglitazone.(5) PPAR-γligands prevented the induction of NF-κB DNA binding activity in response to H_2O_2 in a dose-dependent manner.However, pioglitazone is less effective than 15d-PGJ_2 at the same concentration(10μmol/L). Treatment with the PPAR-γantagonist GW9662 abolished the inhibitory effect on NF-κB activation afforded by pioglitazone,while it did not affect the inhibitory effect afforded by 15d-PGJ_2.(6) 5μmol/L 15d-PGJ_2 stimulated the time-dependent activation of HSF-1 by cardiomyocytes that was first apparent at 3 hours,whereas pioglitazone or H_2O_2 failed to modify the DNA binding ability of HSF-1.(7) H_2O_2-induced IκBαdegradation was attenuated if cardiomyocytes were preincubated for 3 hours with 15d-PGJ_2,or under conditions in which this PPAR-γagonist activated the DNA-binding activity of HSF1.15d-PGJ_2 failed to inhibit H_2O_2-induced IκBαdegradation after a 30-min preincubation when this PPAR-γagonist failed to activate HSF1.(8) 15d-PGJ_2 activated HSF1,and prevented the induction of NF-κB DNA binding activity in response to H_2O_2 in a dose-dependent manner.Treatment with the PPAR-γantagonist GW9662 failed to abolish the effect of 15d-PGJ_2 on HSF1 and NF-κB binding.
Conclusions:(1)Hydrogen peroxide(H_2O_2) as an extracellular source of oxidative stress induced TNF-αand LIX expression via activation of NF-κB in rat cardiac myocytes.(2) Pretreatment of myocytes with PPAR-γligands decreased H_2O_2-induced TNF-αand LIX production(mRNA and protein) in a concentration-dependent manner.(3) 15d-PGJ_2 or pioglitazone inhibits TNF-αand LIX expression through regulation of the NF-κB signaling pathway.(4) The anti-inflammatory effects of 15d-PGJ_2,but not pioglitazone, may be related to the enhance of the heat shock response which,in turn,renders cardiomyocytes unresponsive to stimulation of NF-κB in a PPAR-γ-independent manner.
方法:第一部分:用机械解离法和酶消化法分离培养新生大鼠心室肌细胞,采用差速贴壁分离技术和化学药物抑制法进行纯化。倒置相差显微镜下动态观察细胞形态,台盼蓝染色法测定细胞存活率,并用免疫荧光细胞化学技术鉴定心肌细胞纯度。MTT法检测不同浓度H_2O_2对新生大鼠心肌细胞活力的影响。采用缩时录像机8050对培养的心肌细胞动态进行录像,采集搏动图像,观察搏动情况并计数搏动频率。第二部分:第一部分的基础上,观察H_2O_2在不影响心肌细胞活性的作用浓度下(100μmol/L)诱导细胞分泌炎症介质的效应。采用RT-PCR检测目标炎性因子TNF-α与LIX mRNA水平的表达;ELISA检测细胞培养上清液中TNF-α蛋白含量;Western Blot检测胞浆中LIX和IκBα表达水平。观察PPAR-γ的天然配体15d-PGJ_2与合成配体吡格列酮对TNF-α与LIX表达的影响。利用电泳迁移率变动分析(EMSA)检测H_2O_2对核转录因子NF-κB的效应;Western Blot检测H_2O_2处理组胞浆中IκBα蛋白水平,以及PPAR-γ配体对H_2O_2处理后胞浆中IκBα蛋白表达的影响。同时采用EMSA技术检测15d-PGJ_2与吡格列酮对H_2O_2诱导NF-κB活化的影响;15d-PGJ_2和吡格列酮以及H_2O_2对心肌细胞内热休克转录因子HSF1 DNA结合活性的影响以及与NF-κB信号通路的关系。
结果:第一部分:(1)成功地分离培养原代新生大鼠心室肌细胞,细胞存活率95%以上;差速贴壁分离后,倒置显微镜下观察贴壁后心肌细胞呈梭形、菱形或多角形。8h后即可观察到部分心肌细胞自发性搏动,24h后心肌细胞已全部贴壁,90%以上搏动,48h心肌细胞聚集成簇,细胞搏动趋向同步化。免疫荧光染色鉴定心肌细胞来源及细胞纯度达95%以上,并可见心肌特异性横纹结构。(2)正常培养条件下,在两周不同培养时间内心肌细胞的搏动频率无统计学差异,表明在观察期限内心肌细胞活力保持不变。(3)不同浓度H_2O_2作用心肌细胞48h后,MTT检测的结果显示,10μmol/L和50μmol/L的H_2O_2对心肌细胞活性无影响。100μmol/L的H_2O_2轻微抑制心肌细胞的活性,但无显著性差异(P＞0.05)。200μmol/L的H_2O_2明显抑制心肌细胞活性,具有统计学意义(P＜0.05)。(4)通过采集的搏动图像,观察并记录各处理组心肌细胞的搏动频率后统计结果显示,100μmol/LH_2O_2作用后48h内,对心肌细胞搏动频率无明显影响(P＞0.05),200μmol/L的H_2O_2作用4h后,即显著抑制心肌细胞的搏动频率(P＜0.05),并随时间的延长其抑制效应明显增强(P＜0.01)。第二部分:(1)100μmol/L H_2O_2作用心肌细胞30min后,炎症介质TNF-α和LIX表达开始升高,4h达到峰值后逐渐下降。NF-κB特异性抑制剂SN50明显抑制H_2O_2诱导TNF-α和LIX的生成(P＜0.05)。(2)100μmol/L H_2O_2呈时间依赖性地激活NF-κB,4h时活化达到高峰值(P＜0.01),至8h时逐渐降低(P＜0.05)。H_2O_2升高了胞浆内IκBα磷酸化水平并促进其降解(P＜0.05)。(3)15d-PGJ_2与吡格列酮呈浓度依赖性地抑制H_2O_2诱导的TNF-α与LIXmRNA及蛋白水平的表达(P＜0.05)。(4)5μmol/L 15d-PGJ_2或10μmol/L吡格列酮预处理30min后,二者均未明显抑制H_2O_2诱导的IκBα降解,而延长处理时间至3h时,可以显著升高H_2O_2处理后胞浆内IκBα的蛋白水平(P＜0.05)。(5)PPAR-γ配体以浓度依赖性的方式抑制NF-κB的转录活性,而在相同浓度(10μmol/L)时,15d-PGJ_2的抑制作用强于吡格列酮。同时,PPAR-γ特异性抑制剂GW9662可明显减弱吡格列酮对NF-κB的抑制作用,但未影响15d-PGJ_2对NF-κB的作用。(6)5μmol/L 15d-PGJ_2处理3h时HSF1与其反应元件的结合能力显著增强(P＜0.05),而此时吡格列酮与H_2O_2处理后的心肌细胞中HSF1的活性未见明显改变。(7)15d-PGJ_2处理心肌细胞3h后,激活HSF1的同时可显著抑制H_2O_2诱导的IκBα降解,而在其预处理30min内,HSF1未被明显激活的同时,亦未能有效抑制H_2O_2诱导的IκBα降解。(8)15d-PGJ_2呈浓度依赖性的激活HSF1的同时抑制H_2O_2诱导的NF-κB活化。而且,15d-PGJ_2诱导HSF1活化以及对NF-κB的抑制效应均未被GW9662阻断。
结论:(1)NF-κB信号途径介导了氧化应激诱导大鼠心肌细胞分泌炎性因子TNF-α与LIX。(2)PPAR-γ配体以浓度依赖性的方式抑制心肌细胞分泌TNF-α与LIX。(3)15d-PGJ_2与吡格列酮抑制心肌细胞中NF-κB的转录活性,进而抑制其介导的炎性因子的表达。(4)15d-PGJ_2能以PPAR-γ非依赖性方式提高细胞内热休克反应,抑制氧化应激诱导的炎症反应,在转录水平抑制炎性因子的表达。
Objectives Part one:Hydrogen peroxide(H_2O_2) is a useful tool for studying the inflammatory response induced by reactive oxygen species(ROS) in myocardium.The current study aimed at investigating the properties of primary rat cardiac ventricular myocytes using cell biology technology to record their spontaneous pulsation under time-lapse video microscopy,and inspecting the role of H_2O_2 in cultured cardiomyocytes. Part two:On the basis of part one,this part was designed to evaluate the effects of two distinct ligands of PPAR-γin regulating the inflammatory response induced by oxidative stress,and to examine the potential molecular mechanisms of their cardioprotective effects.
Methods Part one:(1) Neonatal rat cardiomyocytes were isolated with mechanical dissection and enzyme digestion,then purified by means of differential attachment technique and chemical drug inhibition.Morphological changes of cardiomyocytes were observed dynamically with phase-contrast microscopy.The ratio of survival cells was identified by trypan blue staining.The purity of cardiomyocytes was evaluated by immunofluorescence staining with antibody to cardiacα-sarcomeric actin.MTT method was carried out to assay the cell viability when treated with different concentration of H_2O_2.The rhythmic pulsation of the cardiomyocytes was followed microscopically using a time-lapse recorder 8050 before and at various time points during treatment.To count the beating rate,the culture dishes were maintained on the microscope bench.Part two: On the basis of part one,we investigated the effects of a certain concentration of H_2O_2 (100μmol/L) on expression of the proinflammatory cytokine in cardiac myocytes.The expression of TNF-αand LIX mRNA were detected by RT-PCR;the levels of TNF-αin the supematants were measured with commercially available enzyme-linked immunosorbent assay kit;Wwestern blot analysis was performed to detect the LIX and IκBαprotein in the cytoplasm.To investigate whether two chemically unrelated PPAR-γligands,15d-PGJ_2 and pioglitazone could regulate the expression of TNF-αand LIX,the gel electrophoresis mobility shift assay(EMSA) was used to detect the transcriptor factor NF-κB activity under the challenge of H_2O_2 by cardiomyocytes;Western blot analysis was used to detect the effects of 15d-PGJ_2 and pioglitazone on H_2O_2-induced IκBαdegradation;EMSA was performed to determine the effects of PPAR-γligands on the induction of NF-κB DNA binding activity in response to H_2O_2;the effect of 15d-PGJ_2 and pioglitazone or 100μmol/L H_2O_2 on the DNA binding of HSF1,and the relationship between NF-κB and HSF1 signaling pathway were also determined by EMSA.
Results Part one:(1) Primary cultures of neonatal rat cardiac myocytes were prepared from ventricles of Wistar rats.The ratio of survival cells was above 95%. Cardiomyocytes were isolated and purified by means of differential attachment technique. Morphological changes of cardiomyocytes were observed dynamically with phase-contrast microscopy,and the cell shape changed from circles to polygons or fusiform shape after attach along the flask.About 8 hours after plantation,partly cardiomyocytes began to beat spontaneously;after 24 hours all cardiomyocytes had attached and above 90%of them beated.Cardiomyocytes got together and beat synchronously in clusters after 48 hours.The purity of cardiomyocytes was above 95% and cross striation could be observed clearly.(2) Under normal conditions,the beating rate of the cells is no statistical difference at various time points within two weeks.(3) Incubation of cardiomyocytes with various concentrations of H_2O_2 for 48h,MTT analysis showed that there is no decrease in cell viability at concentrations of 10 and 50μmol/L;however,cardiomyocyte viability decreased slightly but not significant at a concentration of 100μmol/L(P＞0.05);200μmol/L H_2O_2 inhibited cell viability significantly(P＜0.05).(4) We recorded the action state of the selected cells using a time-lapse recorder 8050,and analyzed the data.The results indicated that 100μmol/L H_2O_2 has no effect on the beating rate of cell within 48h.After treatment cells with 200μmol/L H_2O_2,the beating rate of cell declined rapidly within 4 hours(P＜0.05),and decreased significantly in a time-dependent manner(P＜0.01)。
Part two:(1)The levels of TNF-αand LIX mRNA were induced within 30 minutes after stimulation with 100μmol/L H_2O_2,remained elevated for 4 hours,and decreased thereafter.The NF-κB-blocking peptide SN50 peptide could inhibit H_2O_2-inducd TNF-αand LIX mRNA expression.(2) Stimulation of cells with H_2O_2(100μmol/L) led to an increase in NF-κB binding activity reaching a plateau at 4 hours and at this time,the amount of IκBαprotein was notably reduced.(3) Both 15d-PGJ_2 and pioglitazone markedly decreased H_2O_2-induced TNF-αand LIX(mRNA and protein) expression in a concentration-dependent manner.(4) Myocytes were pretreated either 30 minutes or 3 hours with 5μmol/L 15d-PGJ_2 or 10μmol/L pioglitazone.Neither 15d-PGJ_2 nor pioglitazone could inhibit H_2O_2-induced IκBαdegradation after a 30-min preincubation, while H_2O_2-induced IκBαdegradation was attenuated if cells were preincubated for 3 hours with 15d-PGJ_2 or pioglitazone.(5) PPAR-γligands prevented the induction of NF-κB DNA binding activity in response to H_2O_2 in a dose-dependent manner.However, pioglitazone is less effective than 15d-PGJ_2 at the same concentration(10μmol/L). Treatment with the PPAR-γantagonist GW9662 abolished the inhibitory effect on NF-κB activation afforded by pioglitazone,while it did not affect the inhibitory effect afforded by 15d-PGJ_2.(6) 5μmol/L 15d-PGJ_2 stimulated the time-dependent activation of HSF-1 by cardiomyocytes that was first apparent at 3 hours,whereas pioglitazone or H_2O_2 failed to modify the DNA binding ability of HSF-1.(7) H_2O_2-induced IκBαdegradation was attenuated if cardiomyocytes were preincubated for 3 hours with 15d-PGJ_2,or under conditions in which this PPAR-γagonist activated the DNA-binding activity of HSF1.15d-PGJ_2 failed to inhibit H_2O_2-induced IκBαdegradation after a 30-min preincubation when this PPAR-γagonist failed to activate HSF1.(8) 15d-PGJ_2 activated HSF1,and prevented the induction of NF-κB DNA binding activity in response to H_2O_2 in a dose-dependent manner.Treatment with the PPAR-γantagonist GW9662 failed to abolish the effect of 15d-PGJ_2 on HSF1 and NF-κB binding.
Conclusions:(1)Hydrogen peroxide(H_2O_2) as an extracellular source of oxidative stress induced TNF-αand LIX expression via activation of NF-κB in rat cardiac myocytes.(2) Pretreatment of myocytes with PPAR-γligands decreased H_2O_2-induced TNF-αand LIX production(mRNA and protein) in a concentration-dependent manner.(3) 15d-PGJ_2 or pioglitazone inhibits TNF-αand LIX expression through regulation of the NF-κB signaling pathway.(4) The anti-inflammatory effects of 15d-PGJ_2,but not pioglitazone, may be related to the enhance of the heat shock response which,in turn,renders cardiomyocytes unresponsive to stimulation of NF-κB in a PPAR-γ-independent manner.
引文
[1]Wang GW,Schuschke DA,Kang YJ.Metallothionein-overexpressing neonatal mouse cardiomyocytes are resistant to H2O2 toxicity.The American journal of physiology,1999,276:H 167-175.
[2]苏燕,李宏伟,张静,修瑞娟.Down-regulation of hepatocyte growth factor mRNA in rat cardiac myocytes under hypoxia mimicked by cobalt chloride.Clinical hemorheology and microcirculation,2006,34:201-206.
[3]王程,李宏伟,李爱玲,张静,修瑞娟.各部位心肌细胞对硝酸酯类药物预适应能力的实验研究.中国病理生理杂志,2006,22:43-48.
[4]贾士东,修瑞娟.心肌细胞功能的研究.中国微循环,2000,4:137-139.
[5]贾士东,李宏伟,张静,修瑞娟.心肌细胞功能的分子微循环学初步实验研究.中国微循环,1999,4:243.
[6]高嵩丹,李宏伟,李爱玲,修瑞娟.Akt介导过氧化氢促新生大鼠心肌细胞肥大.基础医学与临床,2008,2:149-152.
[7]Thandroyen FT,Bellotto D,Katayama A,Hagler HK,Willerson JT,Buja LM.Subcellular electrolyte alterations during progressive hypoxia and following reoxygenation in isolated neonatal rat ventricular myocytes.Circulation research,1992,71:106-119.
[8]Vranova E,Inze D,Van Breusegem F.Signal transduction during oxidative stress.Journal of experimental botany,2002,53:1227-1236.
[9]Kranner I,Cram WJ,Zorn M,Wornik S,Yoshimura I,Stabentheiner E,et al.Antioxidants and photoprotection in a lichen as compared with its isolated symbiotic partners.Proceedings of the National Academy of Sciences of the United States of America,2005,102:3141-3146.
[10]沈静,谢苗荣,徐雍,卢炎,沈潞华.乳鼠心肌细胞培养及纯化方法的改良.中国医药导刊,2001,3:225-226.
[11]董丰,龚开政,张振刚,王波,吕申.原代心肌细胞培养方法的探讨.大连医科大学学报,2001,23:307-308.
[12]王涛,余志斌,谢满江,车红磊.新生大鼠心肌细胞培养技巧.第四军医大学学报,2003,24:封2.
[13]杨晓宁,田宗文,黄焕斌,刘维新,陈锡昌.新生大鼠心肌细胞的体外培养.武汉大学研究生学报(医学版),2004,20:11-13.
[14]Wang C,Li H,Li A,Zhang J,Xiu R.Experimental study on the function of cardiomyocytes.Clinical hemorheology and microcirculation,2003,29:369-374.
[15]牛建立张,朱家麟.培养心肌细胞在心肌损伤模型中的应用.第二军医大学学报 1997,18:192-194.
[16]Harary I,Farley B.In vitro studies of single isolated beating heart cells.Science (New York,NY,1960,131:1674-1675.
[17]Simpson P,Savion S.Differentiation of rat myocytes in single cell cultures with and without proliferating nonmyocardial cells.Cross-striations,ultrastructure,and chronotropic response to isoproterenol.Circulation research,1982,50:101-116.
[18]Thompson EW,Marino TA,Uboh CE,Kent RL,Cooper Gt.Atrophy reversal and cardiocyte redifferentiation in reloaded cat myocardium.Circulation research,1984,54:367-377.
[19]Piper HM,Probst I,Schwartz P,Hutter FJ,Spieckermann PG.Culturing of calcium stable adult cardiac myocytes.Journal of molecular and cellular cardiology,1982,14:397-412.
[20]Dhalla NS,Temsah RM,Netticadan T.Role of oxidative stress in cardiovascular diseases.Journal of hypertension,2000,18:655-673.
[21]Ceriello A,Motz E.Is oxidative stress the pathogenic mechanism underlying insulin resistance,diabetes,and cardiovascular disease?The common soil hypothesis revisited.Arteriosclerosis,thrombosis,and vascular biology,2004,24:816-823.
[22]Mallat Z,Philip I,Lebret M,Chatel D,Maclouf J,Tedgui A.Elevated levels of 8-iso-prostaglandin F2alpha in pericardial fluid of patients with heart failure:a potential role for in vivo oxidant stress in ventricular dilatation and progression to heart failure.Circulation,1998,97:1536-1539.
[23]Valgimigli M,Merli E,Malagutti P,Soukhomovskaia O,Cicchitelli G,Antelli A et al.Hydroxyl radical generation,levels of tumor necrosis factor-alpha,and progression to heart failure after acute myocardial infarction.Journal of the American College of Cardiology,2004,43:2000-2008.
[24]Giordano FJ.Oxygen,oxidative stress,hypoxia,and heart failure.The Journal of clinical investigation,2005,115:500-508.
[25]Hare JM.Oxidative stress and apoptosis in heart failure progression.Circulation research,2001,89:198-200.
[26]Nakagami H,Takemoto M,Liao JK.NADPH oxidase-derived superoxide anion mediates angiotensin Ⅱ-induced cardiac hypertrophy.Journal of molecular and cellular cardiology,2003,35:851-859.
[27]von Harsdorf R,Li PF,Dietz R.Signaling pathways in reactive oxygen species-induced cardiomyocyte apoptosis.Circulation,1999,99:2934-2941.
[1]Houseknecht KL,Cole BM,Steele PJ.Peroxisome proliferator-activated receptor gamma(PPARgamma)and its ligands:a review.Domestic animal endocrinology,2002,22:1-23.
[2]Issemann I,Green S.Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators.Nature,1990,347:645-650.
[3]Rocchi S,Auwerx J.Peroxisome proliferator-activated receptor-gamma:a versatile metabolic regulator.Annals of medicine,1999,31:342-351.
[4]Zingarelli B,Cook JA.Peroxisome proliferator-activated receptor-gamma is a new therapeutic target in sepsis and inflammation.Shock(Augusta,Ga,2005,23:393-399.
[5]Desvergne B,Wahli W.Peroxisome proliferator-activated receptors:nuclear control of metabolism.Endocrine reviews,1999,20:649-688.
[6]Bishop-Bailey D.Peroxisome proliferator-activated receptors in the cardiovascular system.British journal of pharmacology,2000,129:823-834.
[7]Guan Y,Zhang Y,Breyer MD.The Role of PPARs in the Transcriptional Control of Cellular Processes.Drug news & perspectives,2002,15:147-154.
[8]Xu Y,Lu L,Greyson C,Lee J,Gen M,Kinugawa K,et al.Deleterious effects of acute treatment with a peroxisome proliferator-activated receptor-gamma activator in myocardial ischemia and reperfusion in pigs.Diabetes,2003,52:1187-1194.
[9]Vamecq J,Latruffe N.Medical significance of peroxisome proliferator-activated receptors.Lancet,1999,354:141-148.
[10]Naito Y,Yoshikawa T.Thiazolidinediones:a new class of drugs for the therapy of ischemia-reperfusion injury.Drugs Today(Barc),2004,40:423-430.
[11]Chandrasekar B,Smith JB,Freeman GL.Ischemia-reperfusion of rat myocardium activates nuclear factor-KappaB and induces neutrophil infiltration via lipopolysaccharide-induced CXC chemokine.Circulation,2001,103:2296-2302.
[12]Squadrito F,Altavilla D,Zingarelli B,Ioculano M,Calapai G,Campo GM,et al.Tumor necrosis factor involvement in myocardial ischaemia-reperfusion injury.European journal of pharmacology,1993,237:223-230.
[13]Gurevitch J,Frolkis I,Yuhas Y,Lifschitz-Mercer B,Berger E,Paz Y,et al.Anti-tumor necrosis factor-alpha improves myocardial recovery after ischemia and reperfusion.Journal of the American College of Cardiology,1997,30:1554-1561.
[14]Meldrum DR,Dinarello CA,Shames BD,Cleveland JC,Jr.,Cain BS,Banerjee A,et al.Ischemic preconditioning decreases postischemic myocardial tumor necrosis factor-alpha production.Potential ultimate effector mechanism of preconditioning.Circulation,1998,98:11214-218;discussion 11218-219.
[15]Zingarelli B,Sheehan M,Wong HR.Nuclear factor-kappaB as a therapeutic target in critical care medicine.Critical care medicine,2003,31:S105-111.
[16]Shames BD,Barton HH,Reznikov LL,Cairns CB,Banerjee A,Harken AH,et al.Ischemia alone is sufficient to induce TNF-alpha mRNA and peptide in the myocardium.Shock(Augusta,Ga,2002,17:114-119.
[17]Chandrasekar B,Melby PC,Sarau HM,Raveendran M,Perla RP,Marelli-Berg FM,et al.Chemokine-cytokine cross-talk.The ELR+ CXC chemokine LIX(CXCL5)amplifies a proinflammatory cytokine response via a phosphatidylinositol 3-kinase-NF-kappa B pathway.The Journal of biological chemistry,2003,278:4675-4686.
[18]Zhu P,Lu L,Xu Y,Schwartz GG.Troglitazone improves recovery of left ventricular function after regional ischemia in pigs.Circulation,2000,101:1165-1171.
[19]Shiomi T,Tsutsui H,Hayashidani S,Suematsu N,Ikeuchi M,Wen J,et al.Pioglitazone,a peroxisome proliferator-activated receptor-gamma agonist,attenuates left ventricular remodeling and failure after experimental myocardial infarction.Circulation,2002,106:3126-3132.
[20]Wayman NS,Hattori Y,McDonald MC,Mota-Filipe H,Cuzzocrea S,Pisano B,et al.Ligands of the peroxisome proliferator-activated receptors(PPAR-gamma and PPAR-alpha) reduce myocardial infarct size.Faseb J,2002,16:1027-1040.
[21]Ding G,Fu M,Qin Q,Lewis W,Kim HW,Fukai T,et al.Cardiac peroxisome proliferator-activated receptor gamma is essential in protecting cardiomyocytes from oxidative damage.Cardiovasc Res,2007.
[22]Lin YZ,Yao SY,Veach RA,Torgerson TR,Hawiger J.Inhibition of nuclear translocation of transcription factor NF-kappa B by a synthetic peptide containing a cell membrane-permeable motif and nuclear localization sequence.The Journal of biological chemistry,1995,270:14255-14258.
[23]Bowie A,O'Neill LA.Oxidative stress and nuclear factor-kappaB activation:a reassessment of the evidence in the light of recent discoveries.Biochemical pharmacology,2000,59:13-23.
[24]Zingarelli B,Hake PW,Mangeshkar P,O'Connor M,Burroughs T J,Piraino G,et al.Diverse cardioprotective signaling mechanisms of peroxisome proliferator-activated receptor-gamma ligands,15-deoxy-Deltal2,14-prostaglandin J2 and ciglitazone,in reperfusion injury:role of nuclear factor-kappaB,heat shock factor 1,and Akt.Shock (Augusta,Ga,2007,28:554-563.
[25]王程,李宏伟,李爱玲,张静,修瑞娟.各部位心肌细胞对硝酸酯类药物预适应能力的实验研究.中国病理生理杂志,2006,22:43-48.
[26]苏燕,李宏伟,张静,修瑞娟.Down-regulation of hepatocyte growth factor mRNA in rat cardiac myocytes under hypoxia mimicked by cobalt chloride.Clinical hemorheology and microcirculation,2006,34:201-206.
[27]王程,李宏伟,李爱玲,张静,修瑞娟.Experimental study on the function of cardiomyocytes.Clinical hemorheology and microcirculation,2003,29:369-374.
[28]Temsah RM,Netticadan T,Chapman D,Takeda S,Mochizuki S,Dhalla NS.Alterations in sarcoplasmic reticulum function and gene expression in ischemic-reperfused rat heart.The American journal of physiology,1999,277:H584-594.
[29]Dhalla NS,Temsah RM,Netticadan T.Role of oxidative stress in cardiovascular diseases.Journal of hypertension,2000,18:655-673.
[30]Ferrari R,Agnoletti L,Comini L,Gaia G,Bachetti T,Cargnoni A,et al.Oxidative stress during myocardial ischaemia and heart failure.European heart journal,1998,19Suppl B:B2-11.
[31]Chandrasekar B,Streitman JE,Colston JT,Freeman GL.Inhibition of nuclear factor kappa B attenuates proinflammatory cytokine and inducible nitric-oxide synthase expression in postischemic myocardium.Biochimica et biophysica acta,1998,1406:91-106.
[32]Siwik DA,Chang DL,Colucci WS.Interleukin-lbeta and tumor necrosis factor-alpha decrease collagen synthesis and increase matrix metalloproteinase activity in cardiac fibroblasts in vitro.Circulation research,2000,86:1259-1265.
[33]Tracey KJ,Beutler B,Lowry SF,Merryweather J,Wolpe S,Milsark IW,et al.Shock and tissue injury induced by recombinant human cachectin.Science(New York,NY,1986,234:470-474.
[34]Natanson C,Eichenholz PW,Danner RL,Eichacker PQ,Hoffman WD,Kuo GC,et al.Endotoxin and tumor necrosis factor challenges in dogs simulate the cardiovascular profile of human septic shock.The Journal of experimental medicine,1989,169:823-832.
[35]Torre-Amione G,Kapadia S,Lee J,Durand JB,Bies RD,Young JB,et al.Tumor necrosis factor-alpha and tumor necrosis factor receptors in the failing human heart.Circulation,1996,93:704-711.
[36]Herskowitz A,Choi S,Ansari AA,Wesselingh S.Cytokine mRNA expression in postischemic/reperfused myocardium.The American journal of pathology,1995,146:419-428.
[37]Gurevitch J,Frolkis I,Yuhas Y,Paz Y,Matsa M,Mohr R,et al.Tumor necrosis factor-alpha is released from the isolated heart undergoing ischemia and reperfusion.Journal of the American College of Cardiology,1996,28:247-252.
[38]Meldrum DR,Cleveland JC,Jr.,Cain BS,Meng X,Harken AH.Increased myocardial tumor necrosis factor-alpha in a crystalloid-perfused model of cardiac ischemia-reperfusion injury.The Annals of thoracic surgery,1998,65:439-443.
[39]Meng X,Banerjee A,Ao L,Meldrum DR,Cain BS,Shames BD,et al.Inhibition of myocardial TNF-alpha production by heat shock.A potential mechanism of stress-induced cardioprotection against postischemic dysfunction.Annals of the New York Academy of Sciences,1999,874:69-82.
[40]Meldrum DR,Cain BS,Cleveland JC,Jr.,Meng X,Ayala A,Banerjee A,et al.Adenosine decreases post-ischaemic cardiac TNF-alpha production:anti-inflammatory implications for preconditioning and transplantation.Immunology,1997,92:472-477.
[41]Cain BS,Meldrum DR,Meng X,Dinarello CA,Shames BD,Banerjee A,et al.p38 MAPK inhibition decreases TNF-alpha production and enhances postischemic human myocardial function.The Journal of surgical research,1999,83:7-12.
[42]Baggiolini M,Dewald B,Moser B.Interleukin-8 and related chemotactic cytokines--CXC and CC chemokines.Advances in immunology,1994,55:97-179.
[43]Rollins BJ.Chemokines.Blood,1997,90:909-928.
[44]Schall TJ,Bacon KB.Chemokines,leukocyte trafficking,and inflammation.Current opinion in immunology,1994,6:865-873.
[45]Maekawa T,Ishii T.Chemokine/receptor dynamics in the regulation of hematopoiesis.Internal medicine(Tokyo,Japan),2000,39:90-100.
[46]Simonini A,Moscucci M,Muller DW,Bates ER,Pagani FD,Burdick MD,et al. IL-8 is an angiogenic factor in human coronary atherectomy tissue.Circulation,2000,101:1519-1526.
[47]Lukacs NW,Hogaboam C,Campbell E,Kunkel SL.Chemokines:function,regulation and alteration of inflammatory responses.Chemical immunology,1999,72:102-120.
[48]Kukielka GL,Smith CW,LaRosa GJ,Manning AM,Mendoza LH,Daly TJ,et al.Interleukin-8 gene induction in the myocardium after ischemia and reperfusion in vivo.The Journal of clinical investigation,1995,95:89-103.
[49]Yoshie O,Imai T,Nomiyama H.Chemokines in immunity.Advances in immunology,2001,78:57-110.
[50]Choong ML,Yong YP,Tan AC,Luo B,Lodish HF.LIX:a chemokine with a role in hematopoietic stem cells maintenance.Cytokine,2004,25:239-245.
[51]Jordan JE,Zhao ZQ,Vinten-Johansen J.The role of neutrophils in myocardial ischemia-reperfusion injury.Cardiovascular research,1999,43:860-878.
[52]Frangogiannis NG,Youker KA,Entman ML.The role of the neutrophil in myocardial ischemia and reperfusion.Exs,1996,76:263-284.
[53]Natarajan R,Salloum FN,Fisher BJ,Ownby ED,Kukreja RC,Fowler AA,3(rd).Activation of hypoxia-inducible factor-1 via prolyl-4 hydoxylase-2 gene silencing attenuates acute inflammatory responses in postischemic myocardium.American journal of physiology,2007,293:H1571-1580.
[54]Kota BP,Huang TH,Roufogalis BD.An overview on biological mechanisms of PPARs.Pharmacol Res,2005,51:85-94.
[55]Mersmann J,Tran N,Zacharowski PA,Grotemeyer D,Zacharowski K.Rosiglitazone is cardioprotective in a murine model of myocardial I/R.Shock(Augusta,Ga,2008,30:64-68.
[56]Kodera Y,Takeyama K,Murayama A,Suzawa M,Masuhiro Y,Kato S.Ligand type-specific interactions of peroxisome proliferator-activated receptor gamma with transcriptional coactivators.The Journal of biological chemistry,2000,275:33201-33204.
[57]Li M,Pascual G,Glass CK.Peroxisome proliferator-activated receptor gamma-dependent repression of the inducible nitric oxide synthase gene.Molecular and cellular biology,2000,20:4699-4707.
[58]Chung SW,Kang BY,Kim SH,Pak YK,Cho D,Trinchieri G,et al.Oxidized low density lipoprotein inhibits interleukin-12 production in lipopolysaccharide-activated mouse macrophages via direct interactions between peroxisome proliferator-activated receptor-gamma and nuclear factor-kappa B.The Journal of biological chemistry,2000,275:32681-32687.
[59]Willson TM,Brown PJ,Sternbach DD,Henke BR.The PPARs:from orphan receptors to drug discovery.Journal of medicinal chemistry,2000,43:527-550.
[60]Forman BM,Tontonoz P,Chen J,Brun RP,Spiegelman BM,Evans RM.15-Deoxy-delta 12,14-prostaglandin J2 is a ligand for the adipocyte determination factor PPAR gamma.Cell,1995,83:803-812.
[61]Fitzpatrick FA,Wynalda MA.Albumin-catalyzed metabolism of prostaglandin D2.Identification of products formed in vitro.The Journal of biological chemistry,1983, 258:11713-11718.
[62]Kliewer SA,Lenhard JM,Willson TM,Patel I,Morris DC,Lehmann JM.A prostaglandin J2 metabolite binds peroxisome proliferator-activated receptor gamma and promotes adipocyte differentiation.Cell,1995,83:813-819.
[63]Bell-Parikh LC,Ide T,Lawson JA,McNamara P,Reilly M,FitzGerald GA.Biosynthesis of 15-deoxy-deltal2,14-PGJ2 and the ligation of PPARgamma.The Journal of clinical investigation,2003,112:945-955.
[64]Ricote M,Li AC,Willson TM,Kelly CJ,Glass CK.The peroxisome proliferator-activated receptor-gamma is a negative regulator of macrophage activation.Nature,1998,391:79-82.
[65]Chawla A,Barak Y,Nagy L,Liao D,Tontonoz P,Evans RM.PPAR-gamma dependent and independent effects on macrophage-gene expression in lipid metabolism and inflammation.Nature medicine,2001,7:48-52.
[66]Fukushima M.Biological activities and mechanisms of action of PGJ2 and related compounds:an update.Prostaglandins,leukotrienes,and essential fatty acids,1992,47:1-12.
[67]Rossi A,Elia G,Santoro MG.2-Cyclopenten-l-one,a new inducer of heat shock protein 70 with antiviral activity.The Journal of biological chemistry,1996,271:32192-32196.
[68]Bui T,Straus DS.Effects of cyclopentenone prostaglandins and related compounds on insulin-like growth factor-I and Wafl gene expression.Biochimica et biophysica acta,1998,1397:31-42.
[69]Rossi A,Kapahi P,Natoli G,Takahashi T,Chen Y,Karin M,et al.Anti-inflammatory cyclopentenone prostaglandins are direct inhibitors of IkappaB kinase.Nature,2000,403:103-108.
[70]Straus DS,Pascual G,Li M,Welch JS,Ricote M,Hsiang CH,et al.15-deoxy-delta 12,14-prostaglandin J2 inhibits multiple steps in the NF-kappa B signaling pathway.Proceedings of the National Academy of Sciences of the United States of America,2000,97:4844-4849.
[71]Berger J,Bailey P,Biswas C,Cullinan CA,Doebber TW,Hayes NS,et al.Thiazolidinediones produce a conformational change in peroxisomal proliferator-activated receptor-gamma:binding and activation correlate with antidiabetic actions in db/db mice.Endocrinology,1996,137:4189-4195.
[72]Hauner H.The mode of action of thiazolidinediones.Diabetes/metabolism research and reviews,2002,18 Suppl 2:S10-15.
[73]Miyazaki Y,Glass L,Triplitt C,Matsuda M,Cusi K,Mahankali A,et al.Effect of rosiglitazone on glucose and non-esterified fatty acid metabolism in Type Ⅱ diabetic patients.Diabetologia,2001,44:2210-2219.
[74]Miyazaki Y,Mahankali A,Matsuda M,Glass L,Mahankali S,Ferrannini E,et al.Improved glycemic control and enhanced insulin sensitivity in type 2 diabetic subjects treated with pioglitazone.Diabetes care,2001,24:710-719.
[75]Miyazaki Y,Mahankali A,Matsuda M,Mahankali S,Hardies J,Cusi K,et al.Effect of pioglitazone on abdominal fat distribution and insulin sensitivity in type 2 diabetic patients.The Journal of clinical endocrinology and metabolism,2002,87:2784-2791.
[76]Nolan JJ,Ludvik B,Beerdsen P,Joyce M,Olefsky J.Improvement in glucose tolerance and insulin resistance in obese subjects treated with troglitazone.The New England journal of medicine,1994,331:1188-1193.
[77]Murphy GJ,Holder JC.PPAR-gamma agonists:therapeutic role in diabetes,inflammation and cancer.Trends in pharmacological sciences,2000,21:469-474.
[78]Shimabukuro M,Higa S,Shinzato T,Nagamine F,Komiya I,Takasu N.Cardioprotective effects of troglitazone in streptozotocin-induced diabetic rats.Metabolism:clinical and experimental,1996,45:1168-1173.
[79]Khandoudi N,Delerive P,Berrebi-Bertrand I,Buckingham RE,Staels B,Bril A.Rosiglitazone,a peroxisome proliferator-activated receptor-gamma,inhibits the Jun NH(2)-terminal kinase/activating protein 1 pathway and protects the heart from ischemia/reperfusion injury.Diabetes,2002,51:1507-1514.
[80]Thiemermann C,Wayman NS.Menarini Academy Cardiovascular Research Awards in Basic Science 2001:ligands of the orphan receptor peroxisome-proliferator activator-gamma reduce myocardial infarct size.Med Sci Monit,2001,7:787-789.
[81]Yue Tl TL,Chen J,Bao W,Narayanan PK,Bril A,Jiang W,et al.In vivo myocardial protection from ischemia/reperfusion injury by the peroxisome proliferator-activated receptor-gamma agonist rosiglitazone.Circulation,2001,104:2588-2594.
[82]Ito H,Nakano A,Kinoshita M,Matsumori A.Pioglitazone,a peroxisome proliferator-activated receptor-gamma agonist,attenuates myocardial ischemia/reperfusion injury in a rat model.Laboratory investigation;a journal of technical methods and pathology,2003,83:1715-1721.
[83]Mendez M,LaPointe MC.PPARgamma inhibition of cyclooxygenase-2,PGE2 synthase,and inducible nitric oxide synthase in cardiac myocytes.Hypertension,2003,42:844-850.
[84]De Martin R,Hoeth M,Hofer-Warbinek R,Schmid JA.The transcription factor NF-kappa B and the regulation of vascular cell function.Arteriosclerosis,thrombosis,and vascular biology,2000,20:E83-88.
[85]Moynagh PN.The NF-kappaB pathway.Journal of cell science,2005,118:4589-4592.
[86]Santoro MG.Heat shock factors and the control of the stress response.Biochem Pharmacol,2000,59:55-63.
[87]Sarge KD,Zimarino V,Holm K,Wu C,Morimoto RI.Cloning and characterization of two mouse heat shock factors with distinct inducible and constitutive DNA-binding ability.Genes & development,1991,5:1902-1911.
[88]Pirkkala L,Alastalo TP,Zuo X,Benjamin IJ,Sistonen L.Disruption of heat shock factor 1 reveals an essential role in the ubiquitin proteolytic pathway.Molecular and cellular biology,2000,20:2670-2675.
[89]Ianaro A,Ialenti A,Maffia P,Di Meglio P,Di Rosa M,Santoro MG.Anti-inflammatory activity of 15-deoxy-deltal2,14-PGJ2 and 2-cyclopenten-l-one:role of the heat shock response.Molecular pharmacology,2003,64:85-93.
[90]Rossi A,Elia G,Santoro MG.Inhibition of nuclear factor kappa B by prostaglandin Al:an effect associated with heat shock transcription factor activation.Proceedings of the National Academy of Sciences of the United States of America,1997,94:746-750.
[91]Kopp E,Ghosh S.Inhibition of NF-kappa B by sodium salicylate and aspirin.Science(New York,NY,1994,265:956-959.
[92]Rossi A,Elia G,Santoro MG.Activation of the heat shock factor 1 by serine protease inhibitors.An effect associated with nuclear factor-kappaB inhibition.The Journal of biological chemistry,1998,273:16446-16452.
[1]Beamer BA,Negri C,Yen CJ,Gavrilova O,Rumberger JM,Durcan MJ,et al.Chromosomal localization and partial genomic structure of the human peroxisome proliferator activated receptor-gamma(hPPAR gamma)gene.Biochemical and biophysical research communications,1997,233:756-759.
[2]Hsu MH,Palmer CN,Song W,Griffin KJ,Johnson EF.A carboxyl-terminal extension of the zinc finger domain contributes to the specificity and polarity of peroxisome proliferator-activated receptor DNA binding.The Journal of biological chemistry,1998,273:27988-27997.
[3]Desvergne B,Wahli W.Peroxisome proliferator-activated receptors:nuclear control of metabolism.Endocrine reviews,1999,20:649-688.
[4]Olefsky JM.Treatment of insulin resistance with peroxisome proliferator-activated receptor gamma agonists.The Journal of clinical investigation,2000,106:467-472.
[5]Berger J,Moller DE.The mechanisms of action of PPARs.Annual review of medicine,2002,53:409-435.
[6]Vamecq J,Latruffe N.Medical significance of peroxisome proliferator-activated receptors.Lancet,1999,354:141-148.
[7]Lee G,Elwood F,McNally J,Weiszmann J,Lindstrom M,Amaral K,et al.T0070907,a selective ligand for peroxisome proliferator-activated receptor gamma,functions as an antagonist of biochemical and cellular activities.The Journal of biological chemistry,2002,277:19649-19657.
[8]von Knethen A,Brune B.PPARgamma~an important regulator of monocyte/macrophage function.Archivum immunologiae et therapiae experimentalis,2003,51:219-226.
[9]Greene ME,Blumberg B,McBride OW,Yi HF,Kronquist K,Kwan K,et al.Isolation of the human peroxisome proliferator activated receptor gamma cDNA:expression in hematopoietic cells and chromosomal mapping.Gene expression,1995,4:281-299.
[10]Ricote M,Li AC,Willson TM,Kelly CJ,Glass CK.The peroxisome proliferator-activated receptor-gamma is a negative regulator of macrophage activation.Nature,1998,391:79-82.
[11]Chinetti G,Griglio S,Antonucci M,Torra IP,Delerive P,Majd Z,et al.Activation of proliferator-activated receptors alpha and gamma induces apoptosis of human monocyte-derived macrophages.The Journal of biological chemistry,1998,273:25573-25580.
[12]Jiang C,Ting AT,Seed B.PPAR-gamma agonists inhibit production of monocyte inflammatory cytokines.Nature,1998,391:82-86.
[13]Colville-Nash PR,Qureshi SS,Willis D,Willoughby DA.Inhibition of inducible nitric oxide synthase by peroxisome proliferator-activated receptor agonists:correlation with induction of heme oxygenase 1.J Immunol,1998,161:978-984.
[14]Azuma Y,Shinohara M,Wang PL,Ohura K.15-Deoxy-delta(12,14)-prostaglandin J(2)inhibits IL-10 and IL-12 production by macrophages.Biochemical and biophysical research communications,2001,283:344-346.
[15]Inoue H,Tanabe T,Umesono K.Feedback control of cyclooxygenase-2 expression through PPARgamma.The Journal of biological chemistry,2000,275:28028-28032.
[16]Maggi LB,Jr.,Sadeghi H,Weigand C,Scarim AL,Heitmeier MR,Corbett JA.Anti-inflammatory actions of 15-deoxy-delta 12,14-prostaglandin J2 and troglitazone:evidence for heat shock-dependent and-independent inhibition of cytokine-induced inducible nitric oxide synthase expression.Diabetes,2000,49:346-355.
[17]Ishibashi M,Egashira K,Hiasa K,Inoue S,Ni W,Zhao Q,et al.Antiinflammatory and antiarteriosclerotic effects of pioglitazone.Hypertension,2002,40:687-693.
[18]Takata Y,Kitami Y,Yang ZH,Nakamura M,Okura T,Hiwada K.Vascular inflammation is negatively autoregulated by interaction between CCAAT/enhancer-binding protein-delta and peroxisome proliferator-activated receptor-gamma.Circulation research,2002,91:427-433.
[19]Cuzzocrea S,Wayman NS,Mazzon E,Dugo L,Di Paola R,Serraino I,et al.The cyclopentenone prostaglandin 15-deoxy-Delta(12,14)-prostaglandin J(2)attenuates the development of acute and chronic inflammation.Molecular pharmacology,2002,61:997-1007.
[20]Gong P,Stewart D,Hu B,Li N,Cook J,Nel A et al.Activation of the mouse heme oxygenase-1 gene by 15-deoxy-Delta(12,14)-prostaglandin J(2)is mediated by the stress response elements and transcription factor Nrf2.Antioxidants & redox signaling,2002,4:249-257.
[21]Cuzzocrea S,Mazzon E,Dugo L,Patel NS,Serraino I,Di Paola R et al.Reduction in the evolution of murine type Ⅱ collagen-induced arthritis by treatment with rosiglitazone,a ligand of the peroxisome proliferator-activated receptor gamma.Arthritis and rheumatism,2003,48:3544-3556.
[22]Cuzzocrea S,Pisano B,Dugo L,Ianaro A,Britti D,Patel NS,et al.Rosiglitazone,a ligand of the peroxisome proliferator-activated receptor-gamma,reduces acute pancreatitis induced by cerulein.Intensive care medicine,2004,30:951-956.
[23]Ellis CN,Varani J,Fisher GJ,Zeigler ME,Pershadsingh HA,Benson SC,et al.Troglitazone improves psoriasis and normalizes models of proliferative skin disease:ligands for peroxisome proliferator-activated receptor-gamma inhibit keratinocyte proliferation.Archives of dermatology,2000,136:609-616.
[24]Bhagavathula N,Nerusu KC,Lal A,Ellis CN,Chittiboyina A,Avery MA et al.Rosiglitazone inhibits proliferation,motility,and matrix metalloproteinase production in keratinocytes.The Journal of investigative dermatology,2004,122:130-139.
[25]Wang TD,Chen WJ,Lin JW,Chen MF,Lee YT.Effects of rosiglitazone on endothelial function,C-reactive protein,and components of the metabolic syndrome in nondiabetic patients with the metabolic syndrome.The American journal of cardiology,2004,93:362-365.
[26]Marx N,Froehlich J,Siam L,Ittner J,Wierse G,Schmidt A,et al.Antidiabetic PPAR gamma-activator rosiglitazone reduces MMP-9 serum levels in type 2 diabetic patients with coronary artery disease.Arteriosclerosis,thrombosis,and vascular biology,2003,23:283-288.
[27]Marx N,Imhof A,Froehlich J,Siam L,Ittner J,Wierse G,et al.Effect of rosiglitazone treatment on soluble CD40L in patients with type 2 diabetes and coronary artery disease.Circulation,2003,107:1954-1957.
[28]Wang G,Wei J,Guan Y,Jin N,Mao J,Wang X.Peroxisome proliferator-activated receptor-gamma agonist rosiglitazone reduces clinical inflammatory responses in type 2 diabetes with coronary artery disease after coronary angioplasty.Metabolism:clinical and experimental,2005,54:590-597.
[29]Auwerx J.Nuclear receptors.I.PPAR gamma in the gastrointestinal tract:gain or pain?Am J Physiol Gastrointest Liver Physiol,2002,282:G581-585.
[30]Heneka MT,Landreth GE,Hull M.Drug insight:effects mediated by peroxisome proliferator-activated receptor-gamma in CNS disorders.Nature clinical practice,2007,3:496-504.
[31]Malchiodi-Albedi F,Matteucci A,Bernardo A,Minghetti L.PPAR-gamma,Microglial Cells,and Ocular Inflammation:New Venues for Potential Therapeutic Approaches.PPAR research,2008,2008:295784.
[32]Shimabukuro M,Higa S,Shinzato T,Nagamine F,Komiya I,Takasu N.Cardioprotective effects of troglitazone in streptozotocin-induced diabetic rats.Metabolism:clinical and experimental,1996,45:1168-1173.
[33]Khandoudi N,Delerive P,Berrebi-Bertrand I,Buckingham RE,Staels B,Bril A.Rosiglitazone,a peroxisome proliferator-activated receptor-gamma,inhibits the Jun NH(2)-terminal kinase/activating protein 1 pathway and protects the heart from ischemia/reperfusion injury.Diabetes,2002,51:1507-1514.
[34]Zhu P,Lu L,Xu Y,Schwartz GG.Troglitazone improves recovery of left ventricular function after regional ischemia in pigs.Circulation,2000,101:1165-1171.
[35]Wayman NS,Hattori Y,McDonald MC,Mota-Filipe H,Cuzzocrea S,Pisano B,et al.Ligands of the peroxisome proliferator-activated receptors(PPAR-gamma and PPAR-alpha)reduce myocardial infarct size.Faseb J,2002,16:1027-1040.
[36]Thiemermann C,Wayman NS.Menarini Academy Cardiovascular Research Awards in Basic Science 2001:ligands of the orphan receptor peroxisome-proliferator activator-gamma reduce myocardial infarct size.Med Sci Monit,2001,7:787-789.
[37]Yue Tl TL,Chen J,Bao W,Narayanan PK,Bril A,Jiang W,et al.In vivo myocardial protection from ischemia/reperfusion injury by the peroxisome proliferator-activated receptor-gamma agonist rosiglitazone.Circulation,2001,104:2588-2594.
[38]Gonon AT,Bulhak A,Labruto F,Sjoquist PO,Pernow J.Cardioprotection mediated by rosiglitazone,a peroxisome proliferator-activated receptor gamma ligand,in relation to nitric oxide.Basic research in cardiology,2007,102:80-89.
[39]Ito H,Nakano A,Kinoshita M,Matsumori A.Pioglitazone,a peroxisome proliferator-activated receptor-gamma agonist,attenuates myocardial ischemia/reperfusion injury in a rat model.Laboratory investigation;a journal of technical methods and pathology,2003,83:1715-1721.
[40]Liu HR,Tao L,Gao E,Lopez BL,Christopher TA,Willette RN,et al.Anti-apoptotic effects of rosiglitazone in hypercholesterolemic rabbits subjected to myocardial ischemia and reperfusion.Cardiovasc Res,2004,62:135-144.
[41]Tao L,Liu HR,Gao E,Teng ZP,Lopez BL,Christopher TA,et al.Antioxidative, antinitrative,and vasculoprotective effects of a peroxisome proliferator-activated receptor-gamma agonist in hypercholesterolemia.Circulation,2003,108:2805-2811.
[42]Sivarajah A,McDonald MC,Thiemermann C.The cardioprotective effects of preconditioning with endotoxin,but not ischemia,are abolished by a peroxisome proliferator-activated receptor-gamma antagonist.The Journal of pharmacology and experimental therapeutics,2005,313:896-901.
[43]Sidell RJ,Cole MA,Draper NJ,Desrois M,Buckingham RE,Clarke K.Thiazolidinedione treatment normalizes insulin resistance and ischemic injury in the zucker Fatty rat heart.Diabetes,2002,51:1110-1117.
[44]Molavi B,Chen J,Mehta JL.Cardioprotective effects of rosiglitazone are associated with selective overexpression of type 2 angiotensin receptors and inhibition of p42/44 MAPK.American journal of physiology,2006,291:H687-693.
[45]Wynne AM,Mocanu MM,Yellon DM.Pioglitazone mimics preconditioning in the isolated perfused rat heart:a role for the prosurvival kinases PI3K and P42/44MAPK.Journal of cardiovascular pharmacology,2005,46:817-822.
[46]Smeets PJ,Planavila A,van der Vusse GJ,van Bilsen M.Peroxisome proliferator-activated receptors and inflammation:take it to heart.Acta physiologica(Oxford,England),2007,191:171-188.
[47]Zingarelli B,Hake PW,Mangeshkar P,O'Connor M,Burroughs TJ,Piraino G,et al.Diverse cardioprotective signaling mechanisms of peroxisome proliferator-activated receptor-gamma ligands,15-deoxy-Deltal2,14-prostaglandin J2 and ciglitazone,in reperfusion injury:role of nuclear factor-kappaB,heat shock factor 1,and Akt.Shock(Augusta,Ga,2007,28:554-563.
[48]Mersmann J,Tran N,Zacharowski PA,Grotemeyer D,Zacharowski K.Rosiglitazone is cardioprotective in a murine model of myocardial I/R.Shock(Augusta,Ga,2008,30:64-68.
[49]Mendez M,LaPointe MC.PPARgamma inhibition of cyclooxygenase-2,PGE2 synthase,and inducible nitric oxide synthase in cardiac myocytes.Hypertension,2003,42:844-850.
[50]Xu Y,Gen M,Lu L,Fox J,Weiss SO,Brown RD,et al.PPAR-gamma activation fails to provide myocardial protection in ischemia and reperfusion in pigs.American journal of physiology,2005,288:H1314-1323.
[51]Xu Y,Lu L,Greyson C,Lee J,Gen M,Kinugawa K,et al.Deleterious effects of acute treatment with a peroxisome proliferator-activated receptor-gamma activator in myocardial ischemia and reperfusion in pigs.Diabetes,2003,52:1187-1194.
[1]Guan Y,Zhang Y,Breyer MD.The role of PPARs in the transcriptional control of cellular processes[J].Drug News Perspect,2002,15(3):147-154.
[2]Bishop-Bailey D.Peroxisome proliferatoroactivated receptors in the cardiovascular system[J].Br J Pharmacol,2000,129(5):823-834.
[3]Gurnell M.PPAR gamma and metabolism:insights from the study of human genetic variants[J].Clin Endocrinol(Oxf),2003,59(3):267-277.
[4]Desvergne B,Wahli W.Peroxisome proliferator-activated receptors:nuclear control of metabolism[J].Endocr Rev 1999,20(5):649-688.
[5]Vamecq J,Latruffe N.Medical significance of peroxisome proliferator-activated receptors[J].Lancet,1999,354(9173):141-148.
[6]Jiang C,Ting AT,Seed B.PPAR-gamma agonists inhibit production of monocyte inflammatory cytokines[J].Nature,1998,391(6662):82-86.
[7]Ricote M,Li AC,Willson TM,et al The peroxisome proliferator-activated receptor-gamma is a negative regulator of macrophage activation[J].Nature,1998,391(6662):79-82.
[8]Colville-Nash PR,Qureshi SS,Willis D,et al Inhibition of inducible nitric oxide synthase by peroxisome proliferator-activated receptor agonists:correlation with induction of heme oxygenase 1[J].J Immunol,1998,161(2):978-984.
[9]Wang TD,Chen W J,Lin J W,et al Effects of rosiglitazone on endothelial function,C-reactive protein,and components of the metabolic syndrome in nondiabetic patients with the metabolic syndrome[J].Am J Cardiol,2004,93(3):362-365.
[10]Marx N,Froehlich J,Siam L,et al Antidiabetic PPAR gamma-activator rosiglitazone reduces MMP-9 serum levels in type 2 diabetic patients with coronary artery disease[J].Arterioscler Thromb Vasc Biol,2003,23(2):283- 288.
[11]Marx N,Imhof A,Froehlich J,et al Effect of rosiglitazone treatment on soluble CD40L in patients with type 2 diabetes and coronary artery disease[J].Circulation,2003,107(15):1954-1957.
[12]Wang G,Wei J,Guan Y,et al Peroxisome proliferator-activated receptor-gamma agonist rosiglitazone reduces clinical inflammatory responses in type 2 diabetes with coronary artery disease after coronary angioplasty[J].Metabolism,2005,54(5):590-597.
[13]Auwerx,J.Nuclear receptors.I.PPAR gamma in the gastrointestinal tract:gain or pain?[J]Am J Physiol Gastrointest Liver Physiol,2002,282(4):G581-G585.
[14]Heneka M T,Landreth G E,Hull M.Drug insight:effects mediated by peroxisome proliferator-activated receptor-gamma in CNS disorders[J].Nat Clin Pract Neurol,2007,3(9):496-504.
[15]Malchiodi-Albedi F,Matteucci,A,Bernardo,A et al PPAR-gamma,Microglial Cells,and Ocular Inflammation:New Venues for Potential Therapeutic Approaches[J].PPAR Res,2008,1-12.
[16]Shimabukuro M,Higa S,Shinzato T,et al Cardioprotective effects of troglitazone in streptozotocin-induced diabetic rats[J].Metabolism,1996,45(9):1168-1173.
[17]Khandoudi N,Delerive P,Berrebi-Bertrand I,et al Rosiglitazone,a peroxisome proliferator-activated receptorgamma,inhibits the Jun NH(2)-terminal kinase/activating protein 1 pathway and protects the heart from ischemia/reperfusion injury[J].Diabetes,2002,51(5):1507-1514.
[18]Zhu P,Lu L,Xu Y,et al Troglitazone improves recovery of left ventricular function after regional ischemia in pigs[J].Circulation,2000,101(10):1165-11 71.
[19]Wayman NS,Hattori Y,McDonald MC,et al Ligands of the peroxisome proliferator-activated receptors(PPAR-gamma and PPAR-alpha) reduce myocardial infarct size[J].FASEB J,2002,16(9):1027-1040.
[20]Thiemermann C,Wayman NS.Menarini academy cardiovascular research awards in basic science 2001:ligands of the orphan receptor peroxisome-proliferator activator-gamma reduce myocardial infarct size[J].Med Sci Monit,2001,7(4):787-789.
[21]Yue TI TL,Chen J,Bao W,et al In vivo myocardial protection from ischemia/reperfusion injury by the peroxisome proliferator-activated receptor-gamma agonist rosiglitazone[J].Circulation,2001,104(21):2588-2594.
[22]耿登峰,伍卫,金冬梅,等.PPARγ激动剂罗格列酮对心肌缺血再灌注损伤的影响[J].中国病理生理杂志,2005,21(5):872-875.
[23]Ito H,Nakano A,Kinoshita M,et al Pioglitazone,a peroxisome proliferator-activated receptor-gamma agonist,attenuates myocardial ischemia/reperfusion injury in a rat model[J].Lab Invest,2003,83(12):1715-1721.
[24]Liu HR,Tao L,Gao E,et al Anti-apoptotic effects of rosiglitazone in hypercholesterolemic rabbits subjected to myocardial ischemia and reperfusion[J].Cardiovasc Res,2004,62(1):135-144.
[25]Zingarelli B,Hake,P W,Mangeshkar P,et al Diverse cardioprotective signaling mechanisms of peroxisome proliferator-activated receptor-gamma ligands,15-deoxy-Deltal2,14-prostaglandin J2 and ciglitazone,in reperfusion injury:role of nuclear factor-kappaB,heat shock factor 1,and Akt[J].Shock,2007,28(5):554-563.
[26]Mendez M,LaPointe MC PPARy inhibition of cyclooxygenase-2,PGE2 synthase,and inducible nitric oxide synthase in cardiac myocytes[J].Hypertension,2003,42(4):844-850.
[2]苏燕,李宏伟,张静,修瑞娟.Down-regulation of hepatocyte growth factor mRNA in rat cardiac myocytes under hypoxia mimicked by cobalt chloride.Clinical hemorheology and microcirculation,2006,34:201-206.
[3]王程,李宏伟,李爱玲,张静,修瑞娟.各部位心肌细胞对硝酸酯类药物预适应能力的实验研究.中国病理生理杂志,2006,22:43-48.
[4]贾士东,修瑞娟.心肌细胞功能的研究.中国微循环,2000,4:137-139.
[5]贾士东,李宏伟,张静,修瑞娟.心肌细胞功能的分子微循环学初步实验研究.中国微循环,1999,4:243.
[6]高嵩丹,李宏伟,李爱玲,修瑞娟.Akt介导过氧化氢促新生大鼠心肌细胞肥大.基础医学与临床,2008,2:149-152.
[7]Thandroyen FT,Bellotto D,Katayama A,Hagler HK,Willerson JT,Buja LM.Subcellular electrolyte alterations during progressive hypoxia and following reoxygenation in isolated neonatal rat ventricular myocytes.Circulation research,1992,71:106-119.
[8]Vranova E,Inze D,Van Breusegem F.Signal transduction during oxidative stress.Journal of experimental botany,2002,53:1227-1236.
[9]Kranner I,Cram WJ,Zorn M,Wornik S,Yoshimura I,Stabentheiner E,et al.Antioxidants and photoprotection in a lichen as compared with its isolated symbiotic partners.Proceedings of the National Academy of Sciences of the United States of America,2005,102:3141-3146.
[10]沈静,谢苗荣,徐雍,卢炎,沈潞华.乳鼠心肌细胞培养及纯化方法的改良.中国医药导刊,2001,3:225-226.
[11]董丰,龚开政,张振刚,王波,吕申.原代心肌细胞培养方法的探讨.大连医科大学学报,2001,23:307-308.
[12]王涛,余志斌,谢满江,车红磊.新生大鼠心肌细胞培养技巧.第四军医大学学报,2003,24:封2.
[13]杨晓宁,田宗文,黄焕斌,刘维新,陈锡昌.新生大鼠心肌细胞的体外培养.武汉大学研究生学报(医学版),2004,20:11-13.
[14]Wang C,Li H,Li A,Zhang J,Xiu R.Experimental study on the function of cardiomyocytes.Clinical hemorheology and microcirculation,2003,29:369-374.
[15]牛建立张,朱家麟.培养心肌细胞在心肌损伤模型中的应用.第二军医大学学报 1997,18:192-194.
[16]Harary I,Farley B.In vitro studies of single isolated beating heart cells.Science (New York,NY,1960,131:1674-1675.
[17]Simpson P,Savion S.Differentiation of rat myocytes in single cell cultures with and without proliferating nonmyocardial cells.Cross-striations,ultrastructure,and chronotropic response to isoproterenol.Circulation research,1982,50:101-116.
[18]Thompson EW,Marino TA,Uboh CE,Kent RL,Cooper Gt.Atrophy reversal and cardiocyte redifferentiation in reloaded cat myocardium.Circulation research,1984,54:367-377.
[19]Piper HM,Probst I,Schwartz P,Hutter FJ,Spieckermann PG.Culturing of calcium stable adult cardiac myocytes.Journal of molecular and cellular cardiology,1982,14:397-412.
[20]Dhalla NS,Temsah RM,Netticadan T.Role of oxidative stress in cardiovascular diseases.Journal of hypertension,2000,18:655-673.
[21]Ceriello A,Motz E.Is oxidative stress the pathogenic mechanism underlying insulin resistance,diabetes,and cardiovascular disease?The common soil hypothesis revisited.Arteriosclerosis,thrombosis,and vascular biology,2004,24:816-823.
[22]Mallat Z,Philip I,Lebret M,Chatel D,Maclouf J,Tedgui A.Elevated levels of 8-iso-prostaglandin F2alpha in pericardial fluid of patients with heart failure:a potential role for in vivo oxidant stress in ventricular dilatation and progression to heart failure.Circulation,1998,97:1536-1539.
[23]Valgimigli M,Merli E,Malagutti P,Soukhomovskaia O,Cicchitelli G,Antelli A et al.Hydroxyl radical generation,levels of tumor necrosis factor-alpha,and progression to heart failure after acute myocardial infarction.Journal of the American College of Cardiology,2004,43:2000-2008.
[24]Giordano FJ.Oxygen,oxidative stress,hypoxia,and heart failure.The Journal of clinical investigation,2005,115:500-508.
[25]Hare JM.Oxidative stress and apoptosis in heart failure progression.Circulation research,2001,89:198-200.
[26]Nakagami H,Takemoto M,Liao JK.NADPH oxidase-derived superoxide anion mediates angiotensin Ⅱ-induced cardiac hypertrophy.Journal of molecular and cellular cardiology,2003,35:851-859.
[27]von Harsdorf R,Li PF,Dietz R.Signaling pathways in reactive oxygen species-induced cardiomyocyte apoptosis.Circulation,1999,99:2934-2941.
[1]Houseknecht KL,Cole BM,Steele PJ.Peroxisome proliferator-activated receptor gamma(PPARgamma)and its ligands:a review.Domestic animal endocrinology,2002,22:1-23.
[2]Issemann I,Green S.Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators.Nature,1990,347:645-650.
[3]Rocchi S,Auwerx J.Peroxisome proliferator-activated receptor-gamma:a versatile metabolic regulator.Annals of medicine,1999,31:342-351.
[4]Zingarelli B,Cook JA.Peroxisome proliferator-activated receptor-gamma is a new therapeutic target in sepsis and inflammation.Shock(Augusta,Ga,2005,23:393-399.
[5]Desvergne B,Wahli W.Peroxisome proliferator-activated receptors:nuclear control of metabolism.Endocrine reviews,1999,20:649-688.
[6]Bishop-Bailey D.Peroxisome proliferator-activated receptors in the cardiovascular system.British journal of pharmacology,2000,129:823-834.
[7]Guan Y,Zhang Y,Breyer MD.The Role of PPARs in the Transcriptional Control of Cellular Processes.Drug news & perspectives,2002,15:147-154.
[8]Xu Y,Lu L,Greyson C,Lee J,Gen M,Kinugawa K,et al.Deleterious effects of acute treatment with a peroxisome proliferator-activated receptor-gamma activator in myocardial ischemia and reperfusion in pigs.Diabetes,2003,52:1187-1194.
[9]Vamecq J,Latruffe N.Medical significance of peroxisome proliferator-activated receptors.Lancet,1999,354:141-148.
[10]Naito Y,Yoshikawa T.Thiazolidinediones:a new class of drugs for the therapy of ischemia-reperfusion injury.Drugs Today(Barc),2004,40:423-430.
[11]Chandrasekar B,Smith JB,Freeman GL.Ischemia-reperfusion of rat myocardium activates nuclear factor-KappaB and induces neutrophil infiltration via lipopolysaccharide-induced CXC chemokine.Circulation,2001,103:2296-2302.
[12]Squadrito F,Altavilla D,Zingarelli B,Ioculano M,Calapai G,Campo GM,et al.Tumor necrosis factor involvement in myocardial ischaemia-reperfusion injury.European journal of pharmacology,1993,237:223-230.
[13]Gurevitch J,Frolkis I,Yuhas Y,Lifschitz-Mercer B,Berger E,Paz Y,et al.Anti-tumor necrosis factor-alpha improves myocardial recovery after ischemia and reperfusion.Journal of the American College of Cardiology,1997,30:1554-1561.
[14]Meldrum DR,Dinarello CA,Shames BD,Cleveland JC,Jr.,Cain BS,Banerjee A,et al.Ischemic preconditioning decreases postischemic myocardial tumor necrosis factor-alpha production.Potential ultimate effector mechanism of preconditioning.Circulation,1998,98:11214-218;discussion 11218-219.
[15]Zingarelli B,Sheehan M,Wong HR.Nuclear factor-kappaB as a therapeutic target in critical care medicine.Critical care medicine,2003,31:S105-111.
[16]Shames BD,Barton HH,Reznikov LL,Cairns CB,Banerjee A,Harken AH,et al.Ischemia alone is sufficient to induce TNF-alpha mRNA and peptide in the myocardium.Shock(Augusta,Ga,2002,17:114-119.
[17]Chandrasekar B,Melby PC,Sarau HM,Raveendran M,Perla RP,Marelli-Berg FM,et al.Chemokine-cytokine cross-talk.The ELR+ CXC chemokine LIX(CXCL5)amplifies a proinflammatory cytokine response via a phosphatidylinositol 3-kinase-NF-kappa B pathway.The Journal of biological chemistry,2003,278:4675-4686.
[18]Zhu P,Lu L,Xu Y,Schwartz GG.Troglitazone improves recovery of left ventricular function after regional ischemia in pigs.Circulation,2000,101:1165-1171.
[19]Shiomi T,Tsutsui H,Hayashidani S,Suematsu N,Ikeuchi M,Wen J,et al.Pioglitazone,a peroxisome proliferator-activated receptor-gamma agonist,attenuates left ventricular remodeling and failure after experimental myocardial infarction.Circulation,2002,106:3126-3132.
[20]Wayman NS,Hattori Y,McDonald MC,Mota-Filipe H,Cuzzocrea S,Pisano B,et al.Ligands of the peroxisome proliferator-activated receptors(PPAR-gamma and PPAR-alpha) reduce myocardial infarct size.Faseb J,2002,16:1027-1040.
[21]Ding G,Fu M,Qin Q,Lewis W,Kim HW,Fukai T,et al.Cardiac peroxisome proliferator-activated receptor gamma is essential in protecting cardiomyocytes from oxidative damage.Cardiovasc Res,2007.
[22]Lin YZ,Yao SY,Veach RA,Torgerson TR,Hawiger J.Inhibition of nuclear translocation of transcription factor NF-kappa B by a synthetic peptide containing a cell membrane-permeable motif and nuclear localization sequence.The Journal of biological chemistry,1995,270:14255-14258.
[23]Bowie A,O'Neill LA.Oxidative stress and nuclear factor-kappaB activation:a reassessment of the evidence in the light of recent discoveries.Biochemical pharmacology,2000,59:13-23.
[24]Zingarelli B,Hake PW,Mangeshkar P,O'Connor M,Burroughs T J,Piraino G,et al.Diverse cardioprotective signaling mechanisms of peroxisome proliferator-activated receptor-gamma ligands,15-deoxy-Deltal2,14-prostaglandin J2 and ciglitazone,in reperfusion injury:role of nuclear factor-kappaB,heat shock factor 1,and Akt.Shock (Augusta,Ga,2007,28:554-563.
[25]王程,李宏伟,李爱玲,张静,修瑞娟.各部位心肌细胞对硝酸酯类药物预适应能力的实验研究.中国病理生理杂志,2006,22:43-48.
[26]苏燕,李宏伟,张静,修瑞娟.Down-regulation of hepatocyte growth factor mRNA in rat cardiac myocytes under hypoxia mimicked by cobalt chloride.Clinical hemorheology and microcirculation,2006,34:201-206.
[27]王程,李宏伟,李爱玲,张静,修瑞娟.Experimental study on the function of cardiomyocytes.Clinical hemorheology and microcirculation,2003,29:369-374.
[28]Temsah RM,Netticadan T,Chapman D,Takeda S,Mochizuki S,Dhalla NS.Alterations in sarcoplasmic reticulum function and gene expression in ischemic-reperfused rat heart.The American journal of physiology,1999,277:H584-594.
[29]Dhalla NS,Temsah RM,Netticadan T.Role of oxidative stress in cardiovascular diseases.Journal of hypertension,2000,18:655-673.
[30]Ferrari R,Agnoletti L,Comini L,Gaia G,Bachetti T,Cargnoni A,et al.Oxidative stress during myocardial ischaemia and heart failure.European heart journal,1998,19Suppl B:B2-11.
[31]Chandrasekar B,Streitman JE,Colston JT,Freeman GL.Inhibition of nuclear factor kappa B attenuates proinflammatory cytokine and inducible nitric-oxide synthase expression in postischemic myocardium.Biochimica et biophysica acta,1998,1406:91-106.
[32]Siwik DA,Chang DL,Colucci WS.Interleukin-lbeta and tumor necrosis factor-alpha decrease collagen synthesis and increase matrix metalloproteinase activity in cardiac fibroblasts in vitro.Circulation research,2000,86:1259-1265.
[33]Tracey KJ,Beutler B,Lowry SF,Merryweather J,Wolpe S,Milsark IW,et al.Shock and tissue injury induced by recombinant human cachectin.Science(New York,NY,1986,234:470-474.
[34]Natanson C,Eichenholz PW,Danner RL,Eichacker PQ,Hoffman WD,Kuo GC,et al.Endotoxin and tumor necrosis factor challenges in dogs simulate the cardiovascular profile of human septic shock.The Journal of experimental medicine,1989,169:823-832.
[35]Torre-Amione G,Kapadia S,Lee J,Durand JB,Bies RD,Young JB,et al.Tumor necrosis factor-alpha and tumor necrosis factor receptors in the failing human heart.Circulation,1996,93:704-711.
[36]Herskowitz A,Choi S,Ansari AA,Wesselingh S.Cytokine mRNA expression in postischemic/reperfused myocardium.The American journal of pathology,1995,146:419-428.
[37]Gurevitch J,Frolkis I,Yuhas Y,Paz Y,Matsa M,Mohr R,et al.Tumor necrosis factor-alpha is released from the isolated heart undergoing ischemia and reperfusion.Journal of the American College of Cardiology,1996,28:247-252.
[38]Meldrum DR,Cleveland JC,Jr.,Cain BS,Meng X,Harken AH.Increased myocardial tumor necrosis factor-alpha in a crystalloid-perfused model of cardiac ischemia-reperfusion injury.The Annals of thoracic surgery,1998,65:439-443.
[39]Meng X,Banerjee A,Ao L,Meldrum DR,Cain BS,Shames BD,et al.Inhibition of myocardial TNF-alpha production by heat shock.A potential mechanism of stress-induced cardioprotection against postischemic dysfunction.Annals of the New York Academy of Sciences,1999,874:69-82.
[40]Meldrum DR,Cain BS,Cleveland JC,Jr.,Meng X,Ayala A,Banerjee A,et al.Adenosine decreases post-ischaemic cardiac TNF-alpha production:anti-inflammatory implications for preconditioning and transplantation.Immunology,1997,92:472-477.
[41]Cain BS,Meldrum DR,Meng X,Dinarello CA,Shames BD,Banerjee A,et al.p38 MAPK inhibition decreases TNF-alpha production and enhances postischemic human myocardial function.The Journal of surgical research,1999,83:7-12.
[42]Baggiolini M,Dewald B,Moser B.Interleukin-8 and related chemotactic cytokines--CXC and CC chemokines.Advances in immunology,1994,55:97-179.
[43]Rollins BJ.Chemokines.Blood,1997,90:909-928.
[44]Schall TJ,Bacon KB.Chemokines,leukocyte trafficking,and inflammation.Current opinion in immunology,1994,6:865-873.
[45]Maekawa T,Ishii T.Chemokine/receptor dynamics in the regulation of hematopoiesis.Internal medicine(Tokyo,Japan),2000,39:90-100.
[46]Simonini A,Moscucci M,Muller DW,Bates ER,Pagani FD,Burdick MD,et al. IL-8 is an angiogenic factor in human coronary atherectomy tissue.Circulation,2000,101:1519-1526.
[47]Lukacs NW,Hogaboam C,Campbell E,Kunkel SL.Chemokines:function,regulation and alteration of inflammatory responses.Chemical immunology,1999,72:102-120.
[48]Kukielka GL,Smith CW,LaRosa GJ,Manning AM,Mendoza LH,Daly TJ,et al.Interleukin-8 gene induction in the myocardium after ischemia and reperfusion in vivo.The Journal of clinical investigation,1995,95:89-103.
[49]Yoshie O,Imai T,Nomiyama H.Chemokines in immunity.Advances in immunology,2001,78:57-110.
[50]Choong ML,Yong YP,Tan AC,Luo B,Lodish HF.LIX:a chemokine with a role in hematopoietic stem cells maintenance.Cytokine,2004,25:239-245.
[51]Jordan JE,Zhao ZQ,Vinten-Johansen J.The role of neutrophils in myocardial ischemia-reperfusion injury.Cardiovascular research,1999,43:860-878.
[52]Frangogiannis NG,Youker KA,Entman ML.The role of the neutrophil in myocardial ischemia and reperfusion.Exs,1996,76:263-284.
[53]Natarajan R,Salloum FN,Fisher BJ,Ownby ED,Kukreja RC,Fowler AA,3(rd).Activation of hypoxia-inducible factor-1 via prolyl-4 hydoxylase-2 gene silencing attenuates acute inflammatory responses in postischemic myocardium.American journal of physiology,2007,293:H1571-1580.
[54]Kota BP,Huang TH,Roufogalis BD.An overview on biological mechanisms of PPARs.Pharmacol Res,2005,51:85-94.
[55]Mersmann J,Tran N,Zacharowski PA,Grotemeyer D,Zacharowski K.Rosiglitazone is cardioprotective in a murine model of myocardial I/R.Shock(Augusta,Ga,2008,30:64-68.
[56]Kodera Y,Takeyama K,Murayama A,Suzawa M,Masuhiro Y,Kato S.Ligand type-specific interactions of peroxisome proliferator-activated receptor gamma with transcriptional coactivators.The Journal of biological chemistry,2000,275:33201-33204.
[57]Li M,Pascual G,Glass CK.Peroxisome proliferator-activated receptor gamma-dependent repression of the inducible nitric oxide synthase gene.Molecular and cellular biology,2000,20:4699-4707.
[58]Chung SW,Kang BY,Kim SH,Pak YK,Cho D,Trinchieri G,et al.Oxidized low density lipoprotein inhibits interleukin-12 production in lipopolysaccharide-activated mouse macrophages via direct interactions between peroxisome proliferator-activated receptor-gamma and nuclear factor-kappa B.The Journal of biological chemistry,2000,275:32681-32687.
[59]Willson TM,Brown PJ,Sternbach DD,Henke BR.The PPARs:from orphan receptors to drug discovery.Journal of medicinal chemistry,2000,43:527-550.
[60]Forman BM,Tontonoz P,Chen J,Brun RP,Spiegelman BM,Evans RM.15-Deoxy-delta 12,14-prostaglandin J2 is a ligand for the adipocyte determination factor PPAR gamma.Cell,1995,83:803-812.
[61]Fitzpatrick FA,Wynalda MA.Albumin-catalyzed metabolism of prostaglandin D2.Identification of products formed in vitro.The Journal of biological chemistry,1983, 258:11713-11718.
[62]Kliewer SA,Lenhard JM,Willson TM,Patel I,Morris DC,Lehmann JM.A prostaglandin J2 metabolite binds peroxisome proliferator-activated receptor gamma and promotes adipocyte differentiation.Cell,1995,83:813-819.
[63]Bell-Parikh LC,Ide T,Lawson JA,McNamara P,Reilly M,FitzGerald GA.Biosynthesis of 15-deoxy-deltal2,14-PGJ2 and the ligation of PPARgamma.The Journal of clinical investigation,2003,112:945-955.
[64]Ricote M,Li AC,Willson TM,Kelly CJ,Glass CK.The peroxisome proliferator-activated receptor-gamma is a negative regulator of macrophage activation.Nature,1998,391:79-82.
[65]Chawla A,Barak Y,Nagy L,Liao D,Tontonoz P,Evans RM.PPAR-gamma dependent and independent effects on macrophage-gene expression in lipid metabolism and inflammation.Nature medicine,2001,7:48-52.
[66]Fukushima M.Biological activities and mechanisms of action of PGJ2 and related compounds:an update.Prostaglandins,leukotrienes,and essential fatty acids,1992,47:1-12.
[67]Rossi A,Elia G,Santoro MG.2-Cyclopenten-l-one,a new inducer of heat shock protein 70 with antiviral activity.The Journal of biological chemistry,1996,271:32192-32196.
[68]Bui T,Straus DS.Effects of cyclopentenone prostaglandins and related compounds on insulin-like growth factor-I and Wafl gene expression.Biochimica et biophysica acta,1998,1397:31-42.
[69]Rossi A,Kapahi P,Natoli G,Takahashi T,Chen Y,Karin M,et al.Anti-inflammatory cyclopentenone prostaglandins are direct inhibitors of IkappaB kinase.Nature,2000,403:103-108.
[70]Straus DS,Pascual G,Li M,Welch JS,Ricote M,Hsiang CH,et al.15-deoxy-delta 12,14-prostaglandin J2 inhibits multiple steps in the NF-kappa B signaling pathway.Proceedings of the National Academy of Sciences of the United States of America,2000,97:4844-4849.
[71]Berger J,Bailey P,Biswas C,Cullinan CA,Doebber TW,Hayes NS,et al.Thiazolidinediones produce a conformational change in peroxisomal proliferator-activated receptor-gamma:binding and activation correlate with antidiabetic actions in db/db mice.Endocrinology,1996,137:4189-4195.
[72]Hauner H.The mode of action of thiazolidinediones.Diabetes/metabolism research and reviews,2002,18 Suppl 2:S10-15.
[73]Miyazaki Y,Glass L,Triplitt C,Matsuda M,Cusi K,Mahankali A,et al.Effect of rosiglitazone on glucose and non-esterified fatty acid metabolism in Type Ⅱ diabetic patients.Diabetologia,2001,44:2210-2219.
[74]Miyazaki Y,Mahankali A,Matsuda M,Glass L,Mahankali S,Ferrannini E,et al.Improved glycemic control and enhanced insulin sensitivity in type 2 diabetic subjects treated with pioglitazone.Diabetes care,2001,24:710-719.
[75]Miyazaki Y,Mahankali A,Matsuda M,Mahankali S,Hardies J,Cusi K,et al.Effect of pioglitazone on abdominal fat distribution and insulin sensitivity in type 2 diabetic patients.The Journal of clinical endocrinology and metabolism,2002,87:2784-2791.
[76]Nolan JJ,Ludvik B,Beerdsen P,Joyce M,Olefsky J.Improvement in glucose tolerance and insulin resistance in obese subjects treated with troglitazone.The New England journal of medicine,1994,331:1188-1193.
[77]Murphy GJ,Holder JC.PPAR-gamma agonists:therapeutic role in diabetes,inflammation and cancer.Trends in pharmacological sciences,2000,21:469-474.
[78]Shimabukuro M,Higa S,Shinzato T,Nagamine F,Komiya I,Takasu N.Cardioprotective effects of troglitazone in streptozotocin-induced diabetic rats.Metabolism:clinical and experimental,1996,45:1168-1173.
[79]Khandoudi N,Delerive P,Berrebi-Bertrand I,Buckingham RE,Staels B,Bril A.Rosiglitazone,a peroxisome proliferator-activated receptor-gamma,inhibits the Jun NH(2)-terminal kinase/activating protein 1 pathway and protects the heart from ischemia/reperfusion injury.Diabetes,2002,51:1507-1514.
[80]Thiemermann C,Wayman NS.Menarini Academy Cardiovascular Research Awards in Basic Science 2001:ligands of the orphan receptor peroxisome-proliferator activator-gamma reduce myocardial infarct size.Med Sci Monit,2001,7:787-789.
[81]Yue Tl TL,Chen J,Bao W,Narayanan PK,Bril A,Jiang W,et al.In vivo myocardial protection from ischemia/reperfusion injury by the peroxisome proliferator-activated receptor-gamma agonist rosiglitazone.Circulation,2001,104:2588-2594.
[82]Ito H,Nakano A,Kinoshita M,Matsumori A.Pioglitazone,a peroxisome proliferator-activated receptor-gamma agonist,attenuates myocardial ischemia/reperfusion injury in a rat model.Laboratory investigation;a journal of technical methods and pathology,2003,83:1715-1721.
[83]Mendez M,LaPointe MC.PPARgamma inhibition of cyclooxygenase-2,PGE2 synthase,and inducible nitric oxide synthase in cardiac myocytes.Hypertension,2003,42:844-850.
[84]De Martin R,Hoeth M,Hofer-Warbinek R,Schmid JA.The transcription factor NF-kappa B and the regulation of vascular cell function.Arteriosclerosis,thrombosis,and vascular biology,2000,20:E83-88.
[85]Moynagh PN.The NF-kappaB pathway.Journal of cell science,2005,118:4589-4592.
[86]Santoro MG.Heat shock factors and the control of the stress response.Biochem Pharmacol,2000,59:55-63.
[87]Sarge KD,Zimarino V,Holm K,Wu C,Morimoto RI.Cloning and characterization of two mouse heat shock factors with distinct inducible and constitutive DNA-binding ability.Genes & development,1991,5:1902-1911.
[88]Pirkkala L,Alastalo TP,Zuo X,Benjamin IJ,Sistonen L.Disruption of heat shock factor 1 reveals an essential role in the ubiquitin proteolytic pathway.Molecular and cellular biology,2000,20:2670-2675.
[89]Ianaro A,Ialenti A,Maffia P,Di Meglio P,Di Rosa M,Santoro MG.Anti-inflammatory activity of 15-deoxy-deltal2,14-PGJ2 and 2-cyclopenten-l-one:role of the heat shock response.Molecular pharmacology,2003,64:85-93.
[90]Rossi A,Elia G,Santoro MG.Inhibition of nuclear factor kappa B by prostaglandin Al:an effect associated with heat shock transcription factor activation.Proceedings of the National Academy of Sciences of the United States of America,1997,94:746-750.
[91]Kopp E,Ghosh S.Inhibition of NF-kappa B by sodium salicylate and aspirin.Science(New York,NY,1994,265:956-959.
[92]Rossi A,Elia G,Santoro MG.Activation of the heat shock factor 1 by serine protease inhibitors.An effect associated with nuclear factor-kappaB inhibition.The Journal of biological chemistry,1998,273:16446-16452.
[1]Beamer BA,Negri C,Yen CJ,Gavrilova O,Rumberger JM,Durcan MJ,et al.Chromosomal localization and partial genomic structure of the human peroxisome proliferator activated receptor-gamma(hPPAR gamma)gene.Biochemical and biophysical research communications,1997,233:756-759.
[2]Hsu MH,Palmer CN,Song W,Griffin KJ,Johnson EF.A carboxyl-terminal extension of the zinc finger domain contributes to the specificity and polarity of peroxisome proliferator-activated receptor DNA binding.The Journal of biological chemistry,1998,273:27988-27997.
[3]Desvergne B,Wahli W.Peroxisome proliferator-activated receptors:nuclear control of metabolism.Endocrine reviews,1999,20:649-688.
[4]Olefsky JM.Treatment of insulin resistance with peroxisome proliferator-activated receptor gamma agonists.The Journal of clinical investigation,2000,106:467-472.
[5]Berger J,Moller DE.The mechanisms of action of PPARs.Annual review of medicine,2002,53:409-435.
[6]Vamecq J,Latruffe N.Medical significance of peroxisome proliferator-activated receptors.Lancet,1999,354:141-148.
[7]Lee G,Elwood F,McNally J,Weiszmann J,Lindstrom M,Amaral K,et al.T0070907,a selective ligand for peroxisome proliferator-activated receptor gamma,functions as an antagonist of biochemical and cellular activities.The Journal of biological chemistry,2002,277:19649-19657.
[8]von Knethen A,Brune B.PPARgamma~an important regulator of monocyte/macrophage function.Archivum immunologiae et therapiae experimentalis,2003,51:219-226.
[9]Greene ME,Blumberg B,McBride OW,Yi HF,Kronquist K,Kwan K,et al.Isolation of the human peroxisome proliferator activated receptor gamma cDNA:expression in hematopoietic cells and chromosomal mapping.Gene expression,1995,4:281-299.
[10]Ricote M,Li AC,Willson TM,Kelly CJ,Glass CK.The peroxisome proliferator-activated receptor-gamma is a negative regulator of macrophage activation.Nature,1998,391:79-82.
[11]Chinetti G,Griglio S,Antonucci M,Torra IP,Delerive P,Majd Z,et al.Activation of proliferator-activated receptors alpha and gamma induces apoptosis of human monocyte-derived macrophages.The Journal of biological chemistry,1998,273:25573-25580.
[12]Jiang C,Ting AT,Seed B.PPAR-gamma agonists inhibit production of monocyte inflammatory cytokines.Nature,1998,391:82-86.
[13]Colville-Nash PR,Qureshi SS,Willis D,Willoughby DA.Inhibition of inducible nitric oxide synthase by peroxisome proliferator-activated receptor agonists:correlation with induction of heme oxygenase 1.J Immunol,1998,161:978-984.
[14]Azuma Y,Shinohara M,Wang PL,Ohura K.15-Deoxy-delta(12,14)-prostaglandin J(2)inhibits IL-10 and IL-12 production by macrophages.Biochemical and biophysical research communications,2001,283:344-346.
[15]Inoue H,Tanabe T,Umesono K.Feedback control of cyclooxygenase-2 expression through PPARgamma.The Journal of biological chemistry,2000,275:28028-28032.
[16]Maggi LB,Jr.,Sadeghi H,Weigand C,Scarim AL,Heitmeier MR,Corbett JA.Anti-inflammatory actions of 15-deoxy-delta 12,14-prostaglandin J2 and troglitazone:evidence for heat shock-dependent and-independent inhibition of cytokine-induced inducible nitric oxide synthase expression.Diabetes,2000,49:346-355.
[17]Ishibashi M,Egashira K,Hiasa K,Inoue S,Ni W,Zhao Q,et al.Antiinflammatory and antiarteriosclerotic effects of pioglitazone.Hypertension,2002,40:687-693.
[18]Takata Y,Kitami Y,Yang ZH,Nakamura M,Okura T,Hiwada K.Vascular inflammation is negatively autoregulated by interaction between CCAAT/enhancer-binding protein-delta and peroxisome proliferator-activated receptor-gamma.Circulation research,2002,91:427-433.
[19]Cuzzocrea S,Wayman NS,Mazzon E,Dugo L,Di Paola R,Serraino I,et al.The cyclopentenone prostaglandin 15-deoxy-Delta(12,14)-prostaglandin J(2)attenuates the development of acute and chronic inflammation.Molecular pharmacology,2002,61:997-1007.
[20]Gong P,Stewart D,Hu B,Li N,Cook J,Nel A et al.Activation of the mouse heme oxygenase-1 gene by 15-deoxy-Delta(12,14)-prostaglandin J(2)is mediated by the stress response elements and transcription factor Nrf2.Antioxidants & redox signaling,2002,4:249-257.
[21]Cuzzocrea S,Mazzon E,Dugo L,Patel NS,Serraino I,Di Paola R et al.Reduction in the evolution of murine type Ⅱ collagen-induced arthritis by treatment with rosiglitazone,a ligand of the peroxisome proliferator-activated receptor gamma.Arthritis and rheumatism,2003,48:3544-3556.
[22]Cuzzocrea S,Pisano B,Dugo L,Ianaro A,Britti D,Patel NS,et al.Rosiglitazone,a ligand of the peroxisome proliferator-activated receptor-gamma,reduces acute pancreatitis induced by cerulein.Intensive care medicine,2004,30:951-956.
[23]Ellis CN,Varani J,Fisher GJ,Zeigler ME,Pershadsingh HA,Benson SC,et al.Troglitazone improves psoriasis and normalizes models of proliferative skin disease:ligands for peroxisome proliferator-activated receptor-gamma inhibit keratinocyte proliferation.Archives of dermatology,2000,136:609-616.
[24]Bhagavathula N,Nerusu KC,Lal A,Ellis CN,Chittiboyina A,Avery MA et al.Rosiglitazone inhibits proliferation,motility,and matrix metalloproteinase production in keratinocytes.The Journal of investigative dermatology,2004,122:130-139.
[25]Wang TD,Chen WJ,Lin JW,Chen MF,Lee YT.Effects of rosiglitazone on endothelial function,C-reactive protein,and components of the metabolic syndrome in nondiabetic patients with the metabolic syndrome.The American journal of cardiology,2004,93:362-365.
[26]Marx N,Froehlich J,Siam L,Ittner J,Wierse G,Schmidt A,et al.Antidiabetic PPAR gamma-activator rosiglitazone reduces MMP-9 serum levels in type 2 diabetic patients with coronary artery disease.Arteriosclerosis,thrombosis,and vascular biology,2003,23:283-288.
[27]Marx N,Imhof A,Froehlich J,Siam L,Ittner J,Wierse G,et al.Effect of rosiglitazone treatment on soluble CD40L in patients with type 2 diabetes and coronary artery disease.Circulation,2003,107:1954-1957.
[28]Wang G,Wei J,Guan Y,Jin N,Mao J,Wang X.Peroxisome proliferator-activated receptor-gamma agonist rosiglitazone reduces clinical inflammatory responses in type 2 diabetes with coronary artery disease after coronary angioplasty.Metabolism:clinical and experimental,2005,54:590-597.
[29]Auwerx J.Nuclear receptors.I.PPAR gamma in the gastrointestinal tract:gain or pain?Am J Physiol Gastrointest Liver Physiol,2002,282:G581-585.
[30]Heneka MT,Landreth GE,Hull M.Drug insight:effects mediated by peroxisome proliferator-activated receptor-gamma in CNS disorders.Nature clinical practice,2007,3:496-504.
[31]Malchiodi-Albedi F,Matteucci A,Bernardo A,Minghetti L.PPAR-gamma,Microglial Cells,and Ocular Inflammation:New Venues for Potential Therapeutic Approaches.PPAR research,2008,2008:295784.
[32]Shimabukuro M,Higa S,Shinzato T,Nagamine F,Komiya I,Takasu N.Cardioprotective effects of troglitazone in streptozotocin-induced diabetic rats.Metabolism:clinical and experimental,1996,45:1168-1173.
[33]Khandoudi N,Delerive P,Berrebi-Bertrand I,Buckingham RE,Staels B,Bril A.Rosiglitazone,a peroxisome proliferator-activated receptor-gamma,inhibits the Jun NH(2)-terminal kinase/activating protein 1 pathway and protects the heart from ischemia/reperfusion injury.Diabetes,2002,51:1507-1514.
[34]Zhu P,Lu L,Xu Y,Schwartz GG.Troglitazone improves recovery of left ventricular function after regional ischemia in pigs.Circulation,2000,101:1165-1171.
[35]Wayman NS,Hattori Y,McDonald MC,Mota-Filipe H,Cuzzocrea S,Pisano B,et al.Ligands of the peroxisome proliferator-activated receptors(PPAR-gamma and PPAR-alpha)reduce myocardial infarct size.Faseb J,2002,16:1027-1040.
[36]Thiemermann C,Wayman NS.Menarini Academy Cardiovascular Research Awards in Basic Science 2001:ligands of the orphan receptor peroxisome-proliferator activator-gamma reduce myocardial infarct size.Med Sci Monit,2001,7:787-789.
[37]Yue Tl TL,Chen J,Bao W,Narayanan PK,Bril A,Jiang W,et al.In vivo myocardial protection from ischemia/reperfusion injury by the peroxisome proliferator-activated receptor-gamma agonist rosiglitazone.Circulation,2001,104:2588-2594.
[38]Gonon AT,Bulhak A,Labruto F,Sjoquist PO,Pernow J.Cardioprotection mediated by rosiglitazone,a peroxisome proliferator-activated receptor gamma ligand,in relation to nitric oxide.Basic research in cardiology,2007,102:80-89.
[39]Ito H,Nakano A,Kinoshita M,Matsumori A.Pioglitazone,a peroxisome proliferator-activated receptor-gamma agonist,attenuates myocardial ischemia/reperfusion injury in a rat model.Laboratory investigation;a journal of technical methods and pathology,2003,83:1715-1721.
[40]Liu HR,Tao L,Gao E,Lopez BL,Christopher TA,Willette RN,et al.Anti-apoptotic effects of rosiglitazone in hypercholesterolemic rabbits subjected to myocardial ischemia and reperfusion.Cardiovasc Res,2004,62:135-144.
[41]Tao L,Liu HR,Gao E,Teng ZP,Lopez BL,Christopher TA,et al.Antioxidative, antinitrative,and vasculoprotective effects of a peroxisome proliferator-activated receptor-gamma agonist in hypercholesterolemia.Circulation,2003,108:2805-2811.
[42]Sivarajah A,McDonald MC,Thiemermann C.The cardioprotective effects of preconditioning with endotoxin,but not ischemia,are abolished by a peroxisome proliferator-activated receptor-gamma antagonist.The Journal of pharmacology and experimental therapeutics,2005,313:896-901.
[43]Sidell RJ,Cole MA,Draper NJ,Desrois M,Buckingham RE,Clarke K.Thiazolidinedione treatment normalizes insulin resistance and ischemic injury in the zucker Fatty rat heart.Diabetes,2002,51:1110-1117.
[44]Molavi B,Chen J,Mehta JL.Cardioprotective effects of rosiglitazone are associated with selective overexpression of type 2 angiotensin receptors and inhibition of p42/44 MAPK.American journal of physiology,2006,291:H687-693.
[45]Wynne AM,Mocanu MM,Yellon DM.Pioglitazone mimics preconditioning in the isolated perfused rat heart:a role for the prosurvival kinases PI3K and P42/44MAPK.Journal of cardiovascular pharmacology,2005,46:817-822.
[46]Smeets PJ,Planavila A,van der Vusse GJ,van Bilsen M.Peroxisome proliferator-activated receptors and inflammation:take it to heart.Acta physiologica(Oxford,England),2007,191:171-188.
[47]Zingarelli B,Hake PW,Mangeshkar P,O'Connor M,Burroughs TJ,Piraino G,et al.Diverse cardioprotective signaling mechanisms of peroxisome proliferator-activated receptor-gamma ligands,15-deoxy-Deltal2,14-prostaglandin J2 and ciglitazone,in reperfusion injury:role of nuclear factor-kappaB,heat shock factor 1,and Akt.Shock(Augusta,Ga,2007,28:554-563.
[48]Mersmann J,Tran N,Zacharowski PA,Grotemeyer D,Zacharowski K.Rosiglitazone is cardioprotective in a murine model of myocardial I/R.Shock(Augusta,Ga,2008,30:64-68.
[49]Mendez M,LaPointe MC.PPARgamma inhibition of cyclooxygenase-2,PGE2 synthase,and inducible nitric oxide synthase in cardiac myocytes.Hypertension,2003,42:844-850.
[50]Xu Y,Gen M,Lu L,Fox J,Weiss SO,Brown RD,et al.PPAR-gamma activation fails to provide myocardial protection in ischemia and reperfusion in pigs.American journal of physiology,2005,288:H1314-1323.
[51]Xu Y,Lu L,Greyson C,Lee J,Gen M,Kinugawa K,et al.Deleterious effects of acute treatment with a peroxisome proliferator-activated receptor-gamma activator in myocardial ischemia and reperfusion in pigs.Diabetes,2003,52:1187-1194.
[1]Guan Y,Zhang Y,Breyer MD.The role of PPARs in the transcriptional control of cellular processes[J].Drug News Perspect,2002,15(3):147-154.
[2]Bishop-Bailey D.Peroxisome proliferatoroactivated receptors in the cardiovascular system[J].Br J Pharmacol,2000,129(5):823-834.
[3]Gurnell M.PPAR gamma and metabolism:insights from the study of human genetic variants[J].Clin Endocrinol(Oxf),2003,59(3):267-277.
[4]Desvergne B,Wahli W.Peroxisome proliferator-activated receptors:nuclear control of metabolism[J].Endocr Rev 1999,20(5):649-688.
[5]Vamecq J,Latruffe N.Medical significance of peroxisome proliferator-activated receptors[J].Lancet,1999,354(9173):141-148.
[6]Jiang C,Ting AT,Seed B.PPAR-gamma agonists inhibit production of monocyte inflammatory cytokines[J].Nature,1998,391(6662):82-86.
[7]Ricote M,Li AC,Willson TM,et al The peroxisome proliferator-activated receptor-gamma is a negative regulator of macrophage activation[J].Nature,1998,391(6662):79-82.
[8]Colville-Nash PR,Qureshi SS,Willis D,et al Inhibition of inducible nitric oxide synthase by peroxisome proliferator-activated receptor agonists:correlation with induction of heme oxygenase 1[J].J Immunol,1998,161(2):978-984.
[9]Wang TD,Chen W J,Lin J W,et al Effects of rosiglitazone on endothelial function,C-reactive protein,and components of the metabolic syndrome in nondiabetic patients with the metabolic syndrome[J].Am J Cardiol,2004,93(3):362-365.
[10]Marx N,Froehlich J,Siam L,et al Antidiabetic PPAR gamma-activator rosiglitazone reduces MMP-9 serum levels in type 2 diabetic patients with coronary artery disease[J].Arterioscler Thromb Vasc Biol,2003,23(2):283- 288.
[11]Marx N,Imhof A,Froehlich J,et al Effect of rosiglitazone treatment on soluble CD40L in patients with type 2 diabetes and coronary artery disease[J].Circulation,2003,107(15):1954-1957.
[12]Wang G,Wei J,Guan Y,et al Peroxisome proliferator-activated receptor-gamma agonist rosiglitazone reduces clinical inflammatory responses in type 2 diabetes with coronary artery disease after coronary angioplasty[J].Metabolism,2005,54(5):590-597.
[13]Auwerx,J.Nuclear receptors.I.PPAR gamma in the gastrointestinal tract:gain or pain?[J]Am J Physiol Gastrointest Liver Physiol,2002,282(4):G581-G585.
[14]Heneka M T,Landreth G E,Hull M.Drug insight:effects mediated by peroxisome proliferator-activated receptor-gamma in CNS disorders[J].Nat Clin Pract Neurol,2007,3(9):496-504.
[15]Malchiodi-Albedi F,Matteucci,A,Bernardo,A et al PPAR-gamma,Microglial Cells,and Ocular Inflammation:New Venues for Potential Therapeutic Approaches[J].PPAR Res,2008,1-12.
[16]Shimabukuro M,Higa S,Shinzato T,et al Cardioprotective effects of troglitazone in streptozotocin-induced diabetic rats[J].Metabolism,1996,45(9):1168-1173.
[17]Khandoudi N,Delerive P,Berrebi-Bertrand I,et al Rosiglitazone,a peroxisome proliferator-activated receptorgamma,inhibits the Jun NH(2)-terminal kinase/activating protein 1 pathway and protects the heart from ischemia/reperfusion injury[J].Diabetes,2002,51(5):1507-1514.
[18]Zhu P,Lu L,Xu Y,et al Troglitazone improves recovery of left ventricular function after regional ischemia in pigs[J].Circulation,2000,101(10):1165-11 71.
[19]Wayman NS,Hattori Y,McDonald MC,et al Ligands of the peroxisome proliferator-activated receptors(PPAR-gamma and PPAR-alpha) reduce myocardial infarct size[J].FASEB J,2002,16(9):1027-1040.
[20]Thiemermann C,Wayman NS.Menarini academy cardiovascular research awards in basic science 2001:ligands of the orphan receptor peroxisome-proliferator activator-gamma reduce myocardial infarct size[J].Med Sci Monit,2001,7(4):787-789.
[21]Yue TI TL,Chen J,Bao W,et al In vivo myocardial protection from ischemia/reperfusion injury by the peroxisome proliferator-activated receptor-gamma agonist rosiglitazone[J].Circulation,2001,104(21):2588-2594.
[22]耿登峰,伍卫,金冬梅,等.PPARγ激动剂罗格列酮对心肌缺血再灌注损伤的影响[J].中国病理生理杂志,2005,21(5):872-875.
[23]Ito H,Nakano A,Kinoshita M,et al Pioglitazone,a peroxisome proliferator-activated receptor-gamma agonist,attenuates myocardial ischemia/reperfusion injury in a rat model[J].Lab Invest,2003,83(12):1715-1721.
[24]Liu HR,Tao L,Gao E,et al Anti-apoptotic effects of rosiglitazone in hypercholesterolemic rabbits subjected to myocardial ischemia and reperfusion[J].Cardiovasc Res,2004,62(1):135-144.
[25]Zingarelli B,Hake,P W,Mangeshkar P,et al Diverse cardioprotective signaling mechanisms of peroxisome proliferator-activated receptor-gamma ligands,15-deoxy-Deltal2,14-prostaglandin J2 and ciglitazone,in reperfusion injury:role of nuclear factor-kappaB,heat shock factor 1,and Akt[J].Shock,2007,28(5):554-563.
[26]Mendez M,LaPointe MC PPARy inhibition of cyclooxygenase-2,PGE2 synthase,and inducible nitric oxide synthase in cardiac myocytes[J].Hypertension,2003,42(4):844-850.