吡格列酮对SHR心脏成纤维细胞增殖和胶原合成的影响及其与心脏重塑关系的研究
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摘要
目前认为，左心室肥厚是影响原发性高血压患者病残率和病死率的一个重要的独立危险因素。因此，逆转左心室肥厚已成为当前治疗原发性高血压的重要目标之一。左心室肥厚的细胞病理学基础不仅表现在心肌实质细胞的肥大，还有心脏成纤维细胞(CFs)的过度增殖和细胞外基质大量沉积，导致心肌纤维化。原发性高血压心肌纤维化可引起心室功能不全、冠脉储备下降和严重的室性心律失常，使原发性高血压患者发生心力衰竭和猝死的危险显著增加。因此，深入研究间质改建与CFs增殖、胶原合成分泌的关系，采取有效手段抑制或促进间质改建，是改善心脏重构和提高心血管功能的可能途径之一。
目前，国内外学术界公认原发性高血压与内分泌功能紊乱和糖代谢障碍有密切关系，特别是原发性高血压人群有明显的胰岛素抵抗。有学者认为，胰岛素抵抗是原发性高血压的发病原因之一。盐酸吡格列酮(PIO)属于格列酮类新一代胰岛素增敏剂，能够增强胰岛素的敏感性，改善胰岛素抵抗。晚近，国外学术界研究发现格列酮类药物具有强大的心血管保护作用，如抑制血管平滑肌细胞增殖、改善血脂代谢、改善内皮功能、降低纤维蛋白溶解酶原激活抑制物-1和减少动脉粥样硬化发生以及抑制心肌细胞肥大等。但是，关于PIO对于心脏间质细胞有何作用，能否抑制
第四军医大学硕士学位论文
CFs的增殖，逆转心肌纤维化，目前尚不十分清楚。
本研究以培养的自发性高血压大鼠(S HR)和正常血压对照
大鼠(WIStar大鼠)的CFs为试验模型，采用MTT法测定细胞增
殖数目，流式细胞仪(FCM)分析技术检测细胞周期，轻脯氨酸
比色法测定CFs培养上清胶原含量，硝酸还原酶法测定NO浓度，
分光光度法测定NOS活性，免疫组化染色法检测PIO干预下的
SHR CFs中NF一KB表达量。
本课题观察PIO对SHR和Wistar大鼠的CFs增殖和胶原合成
的影响;研究PIO与SHR CFs一氧化氮合酶/一氧化氮伽05一o)
系统活性的关系;探讨PIO调控SHR CFs的NF一KB表达的作用，
旨在阐明PIO逆转心脏重构的作用机制，为防治原发性高血压提
供理论依据和新的方法，同时也为PIO的临床应用提供一个新的
途径。
研究结果表明:(l)不同浓度Plo对sHR、wistar的cFs增
殖均具有抑制作用，且随着浓度的增加，抑制作用逐渐增强，即
具有浓度依赖性。1 x 10一7mol/L、1 x 10一6 mol/L、5 x 10一6 mol/L、
lx1o一sm。比的PIO作用24小时后，SHR的A490值分别为0.19
士0.01、0.18士0.01、0.16士0.01、0.16士0.02，与对照组(0.22
士0.01)相比，具有非常差异性显著(只0.01)。Wistar的A4卯值
分别为0.21士0.01、0.19士0.01、0.18士0.01、0.17士0.01，与
对照组(0.21士0.02)相比，亦具有非常差异性显著(只0.01)。
(2)不同作用时间PIO对SHR、Wistar的CFs亦具有抑制作用，
且随着作用时间的延长，抑制作用逐渐增强，具有时间依赖性。5
xlo一6mo比的PIO作用12h、24h、36h、48h、6oh、72h后，SHR
的A，卯值分别为0.19士0.01、0.16士0.01、0.16士0.02、0.15士0.01、
0.15士0.01、0.15士0.02，同一时间点的对照组A、，。值分别为0.21
士0 .02、0.21士0.01、0.22士0.01、0.23士0.02、0.23士0.01、0.23士
0.02，两者相比，有非常显著性差异(P<0.001)。5 x 10一6 mo比
第四军医大学硕士学位论文
的PIO作用1 Zh、24h、36h、48h、60h、72h后，Wistar的A，，o值
分别为0.19士0.01、0.18士0.01、0.17士0.01、0.16士0.02、0.16士
0.01、0.15士0.01，同一时间点的对照组A妇。值分别为0，20士0.01、
0.21士0.02、0.22士0.02、0.22士0.01、0.23士0、02、0.23士0.01，两
者相比，差异非常显著(P<0.OOI)，其A妇。值亦随着作用时间的
延长而逐渐减低。(3)1 x 10一，mol几、2 x 10一6 mol几、SXlo一6mol几、
lxlo一5 mo比的PIO作用48小时后，SHR、Wistar CFs的G。/
G，期细胞百分率较对照组显著增高(尸均<0.01)，S期细胞百分率、
q/M期细胞百分率和增殖指数则显著低于对照组(尸均<0 .01)，
且随着作用浓度的增加，PIO对细胞周期的影响逐渐增强。(4)不
同浓度PIO对SHR、Wista大鼠CFs培养上清胶原合成具有明显
的抑制作用，随着作用浓度的增加，上清轻脯氨酸含量逐渐降低。
lxlo一7moljL、lxlo一6mol几、5火10一6mol/L、lxzo一smol几的
PIO作用48小时后，SHR CFs上清轻脯氨酸含量为:2.25士0.08、
2.82士0.05、1.35士0.05，2.26士0.07，除lx一。一7mol几的PIO组
和对照组(2 36士0.11)相比，无明显差异(P二0.19)外，余药物
干预组与对照组相比，具有非常显著性差异(尸<0 .01)。Wistar CFs
的上清轻脯氨酸含量为:1.87士0.14、1.76士0.06、1.44士0.05、1.37
士0.09，除1 x 10一7mo比的PIO组和对照组(1 .58士0.16)相比较，
无明显差异(P二0.19)外，余药物干预组与对照组相比，亦有非
常显著性差异(P<0.01)。(5)不同时间PIO对SHR、Wista大鼠
CFs培养上清胶原合成亦具有明显的抑制作用，随着作用时间的
延长，上清轻脯氨酸含量逐渐减低。5 x 10一“mol几的PIO作用24h、
48h、72h后，SHR CFs培养上清经脯氨酸含量分别为:1 .47士0.11、
1.35士0.08、1.43士0.21，与同一时I’ed点的对照组(2.15
Background Left ventricular hypertrophy is regarded as a strong independent risk factor for the morbidity and mortality of essential hypertension. Nowdays the reversal of left ventricular hypertrophy is one of main targets for the treatment of essential hypertension. Besides cardiomyocytes hypertrophy, the pathological basis of left ventricular hypertrophy shows cardiac fibroblasts proliferation and excessive extracellular matrix protein accumulation, which leads to myocardial fibrosis. Hypertensive myocardial fibrosis has been shown to facilitate ventricular dysfunction, diminished coronary reserve and ventricular arrhythmias that adversely affect the clinical outcome of hypertensive patients. Therefore, matrix remodeling is pathologic basis of myocardial remodeling. We should study matrix remodeling carefully and take effective measures to inhibit or promote matrix remodeling, they may give us a possible way to improve cardiovascular function.
Nowadays, the acknowledged concept that the essential hypertension are strongly correlated with insulin resistance. The metabolic syndrome was defined as glucose intolerance, hypertension,
low high-density lipoprotein cholesterol and hypertriglyceridemia. Some believed insulin resistance played an important role in the aetiology of essential hypertension.
Pioglitazone hydrochloride, the thiazolidinediones which are novel insulin-sensitizing agents,as the high affinity ligands for peroxisome proliferator-activated receptor y (PPARy,also as pecific PPARr agonists), has been demonstrated to improve insulin sensitivity so as to attenuate insulin resistance. Recently, studies about thiazolidinediones found that they have the powerful cardiovascular protection, such as attenuate vascular smooth muscle cells prolifertion inhibit pathological cardiac hypertrophy regulate endothelial cell functions ameliorate intriacylglycerol and cholesterol metabolism and reduce plasminogen activator inhibitor-1, and also retard the process of atherosclerosis. Till now, the role of PIO in the pathogenesis of left ventricular hypertrophy associated with hypertension has not been clearly defined. PIO has been proved to attenuate vascular smooth muscle cells prolifertion and inhibit pathological cardiac hypertrophy; however, whether PIO is effective in cardiac interstitium is still obscure.
The aim of this study was to evaluate the antiproliferative effects of PIO on cardiac fibroblasts isolated from SHR and Wistar rat, and its relationship with nitric oxide synthase-nitric oxide system activity and the expressing of NF- k B protein. Furthermore,this studies also want to investigate the effects of PIO on preventing myocardium remodeling so as to provide a valuable theory and. a novel pharmacological strategy for treatment of essential hypertension and find a new way for application of PIO.
Methods Isolated and cultured CFs of SHR and Wistar rats were
used as experiment model. (1) CFs number was measured by MTT assay. FCM determine cell cycle. Collagen content of CFs culture supernatant was estimated by hydroxyproline chromatogragy. We want to investigate the effects of PIO with different concentration and time on proliferation and collagen synthesis of SHR CFs and their relations to cardiac remodeling. (2)Nitrate enzyme reverting method and spectrophotometer were also adopted to estimated the content of NO and activity of NOS in CFs of SHR with or without PIO. We also want to investigate the effects of PIO on the changing of NOS-NO system activity. (3) Using immunohistochemistry, we investigate the effects of PIO on the expressing of NF- k B protein.
Results The results showed that:(1)PIO can inhabit proliferation of CFs from SHR in a concentration-dependent manner with different concentrations of PIO. A490 absorbant value of CFs treated by PIO for 24 hours (1X10-7 1X10-6 5 X 10-6 1X 10-5 mol/L were: SHR 0.19+0. 01 0.18+0. 01 0.16 + 0.01 0.16 + 0.02; Wistar0. 21 + 0. 01 0.19 + 0. 01 0.18 + 0. 01 0.17 + 0. 01) were significantly lower than those of corresponding control groups (0. 22 + 0. 0
目前，国内外学术界公认原发性高血压与内分泌功能紊乱和糖代谢障碍有密切关系，特别是原发性高血压人群有明显的胰岛素抵抗。有学者认为，胰岛素抵抗是原发性高血压的发病原因之一。盐酸吡格列酮(PIO)属于格列酮类新一代胰岛素增敏剂，能够增强胰岛素的敏感性，改善胰岛素抵抗。晚近，国外学术界研究发现格列酮类药物具有强大的心血管保护作用，如抑制血管平滑肌细胞增殖、改善血脂代谢、改善内皮功能、降低纤维蛋白溶解酶原激活抑制物-1和减少动脉粥样硬化发生以及抑制心肌细胞肥大等。但是，关于PIO对于心脏间质细胞有何作用，能否抑制
第四军医大学硕士学位论文
CFs的增殖，逆转心肌纤维化，目前尚不十分清楚。
本研究以培养的自发性高血压大鼠(S HR)和正常血压对照
大鼠(WIStar大鼠)的CFs为试验模型，采用MTT法测定细胞增
殖数目，流式细胞仪(FCM)分析技术检测细胞周期，轻脯氨酸
比色法测定CFs培养上清胶原含量，硝酸还原酶法测定NO浓度，
分光光度法测定NOS活性，免疫组化染色法检测PIO干预下的
SHR CFs中NF一KB表达量。
本课题观察PIO对SHR和Wistar大鼠的CFs增殖和胶原合成
的影响;研究PIO与SHR CFs一氧化氮合酶/一氧化氮伽05一o)
系统活性的关系;探讨PIO调控SHR CFs的NF一KB表达的作用，
旨在阐明PIO逆转心脏重构的作用机制，为防治原发性高血压提
供理论依据和新的方法，同时也为PIO的临床应用提供一个新的
途径。
研究结果表明:(l)不同浓度Plo对sHR、wistar的cFs增
殖均具有抑制作用，且随着浓度的增加，抑制作用逐渐增强，即
具有浓度依赖性。1 x 10一7mol/L、1 x 10一6 mol/L、5 x 10一6 mol/L、
lx1o一sm。比的PIO作用24小时后，SHR的A490值分别为0.19
士0.01、0.18士0.01、0.16士0.01、0.16士0.02，与对照组(0.22
士0.01)相比，具有非常差异性显著(只0.01)。Wistar的A4卯值
分别为0.21士0.01、0.19士0.01、0.18士0.01、0.17士0.01，与
对照组(0.21士0.02)相比，亦具有非常差异性显著(只0.01)。
(2)不同作用时间PIO对SHR、Wistar的CFs亦具有抑制作用，
且随着作用时间的延长，抑制作用逐渐增强，具有时间依赖性。5
xlo一6mo比的PIO作用12h、24h、36h、48h、6oh、72h后，SHR
的A，卯值分别为0.19士0.01、0.16士0.01、0.16士0.02、0.15士0.01、
0.15士0.01、0.15士0.02，同一时间点的对照组A、，。值分别为0.21
士0 .02、0.21士0.01、0.22士0.01、0.23士0.02、0.23士0.01、0.23士
0.02，两者相比，有非常显著性差异(P<0.001)。5 x 10一6 mo比
第四军医大学硕士学位论文
的PIO作用1 Zh、24h、36h、48h、60h、72h后，Wistar的A，，o值
分别为0.19士0.01、0.18士0.01、0.17士0.01、0.16士0.02、0.16士
0.01、0.15士0.01，同一时间点的对照组A妇。值分别为0，20士0.01、
0.21士0.02、0.22士0.02、0.22士0.01、0.23士0、02、0.23士0.01，两
者相比，差异非常显著(P<0.OOI)，其A妇。值亦随着作用时间的
延长而逐渐减低。(3)1 x 10一，mol几、2 x 10一6 mol几、SXlo一6mol几、
lxlo一5 mo比的PIO作用48小时后，SHR、Wistar CFs的G。/
G，期细胞百分率较对照组显著增高(尸均<0.01)，S期细胞百分率、
q/M期细胞百分率和增殖指数则显著低于对照组(尸均<0 .01)，
且随着作用浓度的增加，PIO对细胞周期的影响逐渐增强。(4)不
同浓度PIO对SHR、Wista大鼠CFs培养上清胶原合成具有明显
的抑制作用，随着作用浓度的增加，上清轻脯氨酸含量逐渐降低。
lxlo一7moljL、lxlo一6mol几、5火10一6mol/L、lxzo一smol几的
PIO作用48小时后，SHR CFs上清轻脯氨酸含量为:2.25士0.08、
2.82士0.05、1.35士0.05，2.26士0.07，除lx一。一7mol几的PIO组
和对照组(2 36士0.11)相比，无明显差异(P二0.19)外，余药物
干预组与对照组相比，具有非常显著性差异(尸<0 .01)。Wistar CFs
的上清轻脯氨酸含量为:1.87士0.14、1.76士0.06、1.44士0.05、1.37
士0.09，除1 x 10一7mo比的PIO组和对照组(1 .58士0.16)相比较，
无明显差异(P二0.19)外，余药物干预组与对照组相比，亦有非
常显著性差异(P<0.01)。(5)不同时间PIO对SHR、Wista大鼠
CFs培养上清胶原合成亦具有明显的抑制作用，随着作用时间的
延长，上清轻脯氨酸含量逐渐减低。5 x 10一“mol几的PIO作用24h、
48h、72h后，SHR CFs培养上清经脯氨酸含量分别为:1 .47士0.11、
1.35士0.08、1.43士0.21，与同一时I’ed点的对照组(2.15
Background Left ventricular hypertrophy is regarded as a strong independent risk factor for the morbidity and mortality of essential hypertension. Nowdays the reversal of left ventricular hypertrophy is one of main targets for the treatment of essential hypertension. Besides cardiomyocytes hypertrophy, the pathological basis of left ventricular hypertrophy shows cardiac fibroblasts proliferation and excessive extracellular matrix protein accumulation, which leads to myocardial fibrosis. Hypertensive myocardial fibrosis has been shown to facilitate ventricular dysfunction, diminished coronary reserve and ventricular arrhythmias that adversely affect the clinical outcome of hypertensive patients. Therefore, matrix remodeling is pathologic basis of myocardial remodeling. We should study matrix remodeling carefully and take effective measures to inhibit or promote matrix remodeling, they may give us a possible way to improve cardiovascular function.
Nowadays, the acknowledged concept that the essential hypertension are strongly correlated with insulin resistance. The metabolic syndrome was defined as glucose intolerance, hypertension,
low high-density lipoprotein cholesterol and hypertriglyceridemia. Some believed insulin resistance played an important role in the aetiology of essential hypertension.
Pioglitazone hydrochloride, the thiazolidinediones which are novel insulin-sensitizing agents,as the high affinity ligands for peroxisome proliferator-activated receptor y (PPARy,also as pecific PPARr agonists), has been demonstrated to improve insulin sensitivity so as to attenuate insulin resistance. Recently, studies about thiazolidinediones found that they have the powerful cardiovascular protection, such as attenuate vascular smooth muscle cells prolifertion inhibit pathological cardiac hypertrophy regulate endothelial cell functions ameliorate intriacylglycerol and cholesterol metabolism and reduce plasminogen activator inhibitor-1, and also retard the process of atherosclerosis. Till now, the role of PIO in the pathogenesis of left ventricular hypertrophy associated with hypertension has not been clearly defined. PIO has been proved to attenuate vascular smooth muscle cells prolifertion and inhibit pathological cardiac hypertrophy; however, whether PIO is effective in cardiac interstitium is still obscure.
The aim of this study was to evaluate the antiproliferative effects of PIO on cardiac fibroblasts isolated from SHR and Wistar rat, and its relationship with nitric oxide synthase-nitric oxide system activity and the expressing of NF- k B protein. Furthermore,this studies also want to investigate the effects of PIO on preventing myocardium remodeling so as to provide a valuable theory and. a novel pharmacological strategy for treatment of essential hypertension and find a new way for application of PIO.
Methods Isolated and cultured CFs of SHR and Wistar rats were
used as experiment model. (1) CFs number was measured by MTT assay. FCM determine cell cycle. Collagen content of CFs culture supernatant was estimated by hydroxyproline chromatogragy. We want to investigate the effects of PIO with different concentration and time on proliferation and collagen synthesis of SHR CFs and their relations to cardiac remodeling. (2)Nitrate enzyme reverting method and spectrophotometer were also adopted to estimated the content of NO and activity of NOS in CFs of SHR with or without PIO. We also want to investigate the effects of PIO on the changing of NOS-NO system activity. (3) Using immunohistochemistry, we investigate the effects of PIO on the expressing of NF- k B protein.
Results The results showed that:(1)PIO can inhabit proliferation of CFs from SHR in a concentration-dependent manner with different concentrations of PIO. A490 absorbant value of CFs treated by PIO for 24 hours (1X10-7 1X10-6 5 X 10-6 1X 10-5 mol/L were: SHR 0.19+0. 01 0.18+0. 01 0.16 + 0.01 0.16 + 0.02; Wistar0. 21 + 0. 01 0.19 + 0. 01 0.18 + 0. 01 0.17 + 0. 01) were significantly lower than those of corresponding control groups (0. 22 + 0. 0
引文
[1] 林金秀，陈达光，谢良地，郑舒亮，吴可贵．原发性高血压患者胰岛素抵抗与其他代谢异常的关系[J]．中华心血管病杂志，2000，28(3)：170-172．
[2] 李光伟．高血压与糖尿病-代谢综合症的两柄利剑[J]．高血压杂志，2003，(11)1：3-4．
[3] 孙凯，张红叶，田秀珍，池丽珠，任福秀，王颖玲，黄晓红．高血压大家系中胰岛素抵抗与高血压关系的研究[J]．高血压杂志，2003，11(1)：54-57．
[4] 李光伟，杨文英，洪靖，李春梅，孙淑湘，蔡慧，王金平．胰岛素抵抗—遗传和环境因素致高血压的共同途径?[J]．中华内科杂志，2003，42(1)：11-15．
[5] 包玉倩，贾伟平，陆俊茜，陈莹，项坤三．中国人高血压个体胰岛素抵抗的影响因素[J]．中华心血管病杂志，2002，30(8)：483-486．
[6] Nash DT. Insulin Resistance, ADMA level, and Cardiovascular Disease[J]. JAMA,2002,287(11): 1451-1452.
[7] Zimmet PZ,McCarty DJ,de-Courten-MP, Reaven GM, Kaplan NM.The global epidemiology of non-insulin-dependent diabetes mellitus and the metabolic syndrome. J-Diabetes-Complications 1997,11(2):60
[8] David JG, Carol RD,Deborah S, Sugiyama Y, Ikeda H.Liver Enzyme Monitoring in Pations Treated with Troglitazone. JAMA2001 ;286:831-833.
[9] Hanefeld M, Belcher G. Safety profile of pioglitazone. Int J Clin Pract Suppl 2001 Sep;(121):27-31
[10] Henriksson F. Applications of economic models in healthcare: the introduction of pioglitazone in Sweden. Pharmacoeconomics 2002;20 Suppl 1:43-53
[11] Coyle D, Palmer AJ, Tam R. Economic evaluation of
pioglitazone, hydrochloride in the management of type 2 diabetes mellitus in Canada. Pharmacoeconomics 2002;20 Suppl 1:31-42
[12] Isseman I,Green S. Activation of a member of the steroid hormone receptor superfamily by Peroxisome Proliferators.Nature 1990,347:645-650
[13] Tugwood J, Isseman I,Green S. Sugiyama Y, Ikeda H.The mouse Peroxisome Proliferator-Activated Receptor recognize a response element in the flanking of the rat acry-CoA oxidese gene. EMBO J,1992,11:433-439
[14] Baba S. Pioglitazone: a review of Japanese clinical studies: ACTOS Clinical Studies in Japan. Curr Med Res Opin 2001;17(3):166-89
[15] Hanefeld M. Pharmacokinetics and clinical efficacy of pioglitazone. Int J Clin Pract Suppl 2001 Sep;(121):19-25
[16] Lebovitz HE. Differentiating members of the thiazolidinedione class: a focus on safety. Diabetes Metab Res Rev 2002 Mar-Apr;18 Suppl 2:S23-9
[17] Suzuki M, Odaka H, Suzuki N, Sugiyama Y, Ikeda H. Effects of combined pioglitazone and metformin on diabetes and obesity in Wistar fatty rats. Clin Exp Pharmacol Physiol 2002 Apr;29(4):269-74
[18] Goldstein BJ. Differentiating members of the thiazolidinedione class: a focus on efficacy. Diabetes Metab Res Rev 2002 Mar-Apr;18 Suppl 2:S16-22
[19] Einhorn D, Rendell M, Rosenzweig J, Egan JW, Mathisen AL, Schneider RL. Pioglitazone hydrochloride in combination with metformin in the treatment of type 2 diabetes mellitus: a randomized, placebo-controlled study。The Pioglitazone 027 Study Group. Clin Ther 2000 Dec;22(12):1395-409
[20] King AB, Armstrong DU. Lipid response to pioglitazone in diabetic patients: clinical observations from a retrospective chart review. Diabetes Teclmol Ther 2002;4(2):145-51
[21] Miyazaki Y, Mahankali A, Matsuda M, Mahankali S, Hardies J, Cusi K, Mandadno LJ, DeFronzo RA. Effect of pioglitazone on abdominal fat distribution and insulin sensitivity in type 2 diabetic patients. J Clin Endocrinol Metab 2002 Jun; 87(6): 2784-91
[22] Boyle PJ, King AB, Olansky L, Marchetti A, Lau H, Magar R, Martin J. Effects of pioglitazone and rosiglitazone on blood lipid levels and glycemic control in patients with type 2 diabetes mellitus: a retrospective review of randomly selected medical records. Clin Ther 2002 Mar;24(3):378-96
[23] Khan MA, St Peter JV, Xue JL. A prospective, randomized comparison of the metabolic effects of pioglitazone or rosiglitazone in patients with type 2 diabetes who were previously treated with troglitazone. Diabetes Care 2002 Apr;25(4):708-11
[24] Hirose H, Kawai T, Yamamoto Y, Taniyama M, Tomita M, Matsubara K, Okazaki Y, Ishii T, Oguma Y, Takei I, Saruta T. Effects of pioglitazone on metabolic parameters, body fat distribution, and serum adiponectin levels in Japanese male patients with type 2 diabetes. Metabolism 2002 Mar;51(3):314-7
[25] Tan MH.Current treatment of insulin resistance in type 2 diabetes mellitus. Int J Clin Pratt Suppl 2000 Oct;(113):54-62
[26] Smith U. Pioglitazone: mechanism of action. Int J Clin Pract Suppl 2001 Sep;(121):13-8
[27] Smith U, Gogg S, Johansson A, Olausson T, Rotter V, Svalstedt B. Thiazolidinediones (PPARgamma agonists) but not PPARalpha agonists increase IRS-2 gene expression in 3T3-L1 and human
adipocytes. FASEB J 2001 Jan;15(1):215-220.
[28] Qi N, Kazdova L, Zidek V, Landa V, Kren V, Pershadsingh HA, St Lezin E, Abumrad NA, Pravenec M, Kurtz TW.Pharmacogenetic evidence that Cd36 is a key determinant of the metabolic effects of pioglitazone.J Biol Chem 2002 Oct 15;
[29] Suzuki M, Odaka H, Suzuki N, Sugiyama Y, Ikeda H. Effects of combined pioglitazone and metformin on diabetes and obesity in Wistar fatty rats. Clin Exp Pharmacol Physiol 2002 Apr; 29(4):269-74.
[30] Keiji Yamamoto,Ruri Ohki,Richard T.Lee,Taniyama M, Tomita M, Matsubara K, Okazaki Y, Ishii T, Oguma Y, Takei I, Saruta T. Peroxisome Proliferator-Activated Receptor γ Activators inhibit cardiac hypertrophy in cardiac myocytes.Circulation 2001; 104 (14):1670—1675
[31] Sakai S, Miyauchi T, Irukayama-Tomobe Y, Ogata T, Goto K, Yamaguchi I.Peroxisome proliferator-activated receptor-gamma activators inhibit endothelin-1-related cardiac hypertrophy in rats. Clin Sci (Lond) 2002 Sep 1;103 Suppl 1:16S-20S
[32] Masayuki A,Hiroyuki T, Toshio N,Hiroki U,Hiroshi H,Naoto K, Toshihiro S,Issei K. Peroxisome Proliferator-Activated Receptor γ Plays a Critical Role in Inhibition of cardiac hypertrophy in Vitro and inVivo. Circulation 2002; 105: 1240-1246.
[33] Igarashi M, Hirata A, Yamaguchi H, Tsuchiya H, Ohnuma H, Tominaga M, Daimon M, Kato T. Characterization of an inhibitory effect of pioglitazone on balloon-injured vascular smooth muscle cell growth.. Metabolism 2001 Aug;50(8):955-62)
[34] Aizawa Y, Kawabe J, Hasebe N, Takehara N, Kikuchi K. Pioglitazone enhances cytokine-induced apoptosis in vascular smooth
muscle cells and reduces intimal hyperplasia.. Circulation 2001 Jul 24;104(4):455-60)
[35] Ishibashi M, Egashira K, Hiasa K, Inoue S, Ni W, Zhao Q, Usui M, Kitamoto S, Ichiki T, Takeshita A. Antiinflammatory and antiarteriosclerotic effects of pioglitazone.. Hypertension 2002 Nov;40(5):687-93)
[36] Tian-li Yue,PhD;Jun Chen, MS;Weike Bao,MD;Padma KN,PhD; Antoine B,PhD;Wen Jiang,MD;Paul GL,MD,In Vivo Myocardial Protection From Ischemia/Reperfusion Injury by the Peroxisome Proliferator-Activated Receptor γ Agonist Rosiglitazone. Circulation 2001; 104: 2588-2594。
[37] 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. Lab Invest. 2003 Dec;83(12):1715-21.
[38] Wayman NS, Hattori Y, McDonald MC, Mota-Filipe H, Cuzzocrea S, Pisano B, Chatterjee PK, Thiemermann C. Ligands of the peroxisome proliferator-activated receptors (PPAR-gamma and PPAR-alpha) reduce myocardial infarct size. FASEB J 2002 Jul; 16(9): 1027-40。
[39] 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 May;51(5):1507-14
[40] Delerive P, Fruchart JC, Staels B. Faveeuw C, Fougeray S, Angeli V, Fontaine J, Chinetti G, Gosset P,Maliszewski C, Capron M, Moser M, Trottein F..Peroxisome proliferator-activated receptors in
inflammation control. J Endocrinol 2001 Jun;169(3):453.
[41] Cemuda-Morollon E, Rodriguez-Pascual F, Klatt P, Lamas S, Perez-Sala D. PPAR Agonists Amplify iNOS Expression While Inhibiting NF-kappaB: Implications for Mesangial Cell Activation by Cytokines. J Am Soc Nephrol. 2002 Sep; 13(9):2223-31。
[42] Haffner SM, Greenberg AS, Weston WM,Chen H,Williams K, Freed MI. Effect of rosiglitazone treatment on nontraditional markers of cardiovascular disease in patients with type 2 diabetes mellitus. Circulation 2002 Aug 6;106(6):679-84
[43] Nikolaus Marx, Bettina Kehrle, Klaus Kohlhammer, Miriam Grub,Wolfgang Koenig,Vinzenz Hombach,Peter Libby, Jorge Plutzky. PPAR Activators as Antiinflammatory Mediators in Human T Lymphocytes. Circ Res.2002;90:703-710.
[44] Stuhlinger MC,Abbasi F, Chu JW.Lamendola C,McLaughlin TL,Cooke JP, Reaven GM,Tsao PS.Relationship Between Insulin Resistance and an Endogenous Nitric Oxide Synthese Inhibitor. JAMA2002, 287(11): 1420—1426
[45] Dobrian AD, Schriver SD, Khraibi AA, Prewitt RL.Pioglitazone prevents hypertension and reduces oxidative stress in diet-induced obesity. Hypertension. 2004 Jan;43(1):48-56. Epub 2003 Nov 24.
[46] Fullert S, Schneider F, Haak E, Rau H, Badenhoop K, Lubben G, Usadel KH, Konrad T. Effects of pioglitazone in nondiabetic patients with arterial hypertension: a double-blind, placebo-controlled study. J Clin Endocrinol Metab. 2002 Dec;87(12):5503-6.
[47] Gerber P, Lubben G, Heusler S, Dodo A. Effects of pioglitazone on metabolic control and blood pressure: a randomised study in patients with type 2 diabetes mellitus. Curr Med Res Opin. 2003;19(6):532-9.
[48] Roberts AW, Thomas A,Rees A,Evans M.Peroxisome proliferator-activated receptor-gamma agonists in atherosclerosis: current evidence and future directions. Curr Opin Lipidol. 2003 Dec;14(6):567-73.
[49] Tsuji T, Mizushige K, Noma T, Murakami K, Ohmori K, Miyatake A, Kohno M. Pioglitazone improves left ventricular diastolic function and decreases collagen accumulation in prediabetic stage of a type Ⅱ diabetic rat. J Cardiovasc Pharmacol 2001 Dec;38(6):868-74.
[50] Kim SK, Zhao ZS, Lee YJ, Lee KE, Kang SM, Choi D, Lim SK, Chung N, Lee HC, Cha BS. Left-ventricular diastolic dysfunction may be prevented by chronic treatment with PPAR-alpha or -gamma agonists in a type 2 diabetic animal model. Diabetes Metab Res Rev. 2003 Nov-Dee; 19(6):487-93.
[51] Winkler K, Konrad T, Fullert S, Friedrich I, Destani R, Baumstark MW, Krebs K, Wieland H, Marz W. Pioglitazone reduces atherogenic dense LDL particles in nondiabetic patients with arterial hypertension: a double-blind, placebo-controlled study.Diabetes Care. 2003 Sep;26(9):2588-94.
[52] Stumvoll M, Hating HU. Glitazones: clinical effects and molecular mechanisms. Ann Med 2002;34(3):217-24
[53] Meier C, Chicheportiche R, Juge-Aubry C, Dreyer M, Dayer J. Regulation of the interleukin-1 receptor antagonist in THP-1 cells by ligands of the peroxisome proliferator-activated receptor gamma.. Cytokine 2002 Jun 21;18(6):320
[54] Shiojiri T, Wada K, Nakajima A, Katayama K, Shibuya A, Kudo C, Kadowaki T, Mayumi T, Yura Y, Kamisaki Y. PPARgamma ligands inhibit, nitrotyrosine formation and inflammatory mediator expressions in adjuvant-induced rheumatoid arthritis mice..Eur J
Pharmacol 2002 Jul 19;448(2-3):231-8
[55] Iida KT, Kawakami Y, Suzuki H, Sone H, Shimano H, Toyoshima H, Okuda Y, Yamada N. PPAR gamma ligands, troglitazone and pioglitazone, up-regulate expression of HMG-CoA synthase and HMG-CoA reductase gene in THP-1 macrophages. FEBS Lett 2002 Jun 5;520(1-3):177-81
[56] Galli A, Crabb DW, Ceni E, Salzano R, Mello T, Svegliati-Baroni G, Ridolfi F, Trozzi L, Surrenti C, Casini A. Antidiabetic thiazolidinediones inhibit collagen synthesis and hepatic stellate cell activation in vivo and in vitro. Gastroenterology 2002 Jun; 122(7): 1924-40
[57] Kon K, Ikejima K, Hirose M, Yoshikawa M, Enomoto N, Kitamura T, Takei Y, Sato N. Yoshikawa M, Enomoto N, Kitamura T, Takei Y, Sato N.Pioglitazone prevents early-phase hepatic fibrogenesis caused by carbon tetrachloride. Biochem Biophys Res Commun 2002 Feb 15;291(1):55-61.
[58] Kawaguchi K, Sakaida I, Tsuchiya M, Omori K, Takami T, Okita K. Pioglitazone prevents hepatic steatosis, fibrosis, and enzyme-altered lesions in rat liver cirrhosis induced by a choline-deficient L-amino acid-defined diet. Biochem Biophys Res Commun. 2004 Feb 27;315(1):187-95.
[59] Kawakami S, Arai G, Hayashi T, Fujii Y, Xia G; Kageyama Y, Kihara K. PPARgamma ligands suppress proliferation of human urothelial basal cells in vitro. J Cell Physiol 2002 Jun;191(3):310-9
[60] Nakamuta M, Enjoji M, Uchimura K, Ohta S, Sugimoto R, Kotoh K, Kato M, Irie T, Muta T, Nawata H. Bisphenol A diglycidyl ether (BADGE)supprwsses tumor necrosis factor-α(TNF-α)production as a PPARgamma agonist in the murine macrophage-like cell line
RAW 264.7. Cell Biol Int 2002;26(3):235-41
[61] Nakamura T, Ushiyama C, Osada S, Hara M, Shimada N, Koide H. Pioglitazone reduces urinary podocyte excretion in type 2 diabetes patients with microalbuminuria.Metabolism 2001 Oct;50(10): 1193-6
[62] Yanagawa T, Araki A, Sasamoto K, Shirabe S, Yamanouchi T. Effect of antidiabetic medications on microalbuminuria in patients with type 2 diabetes. Metabolism. 2004 Mar;53(3):353-7.
[63] Feinstein DL, Galea E, Gavrilyuk V, Brosnan CF, Whitacre CC, Dumitrescu-Ozimek L, Landreth GE, Pershadsingh HA, Weinberg G, Heneka MT. Peroxisome proliferator-activated receptor-gamma agonists prevent experimental autoimmune encephalomyelitis,。Ann Neurol 2002 Jun;51(6):694-702
[64] Kasono K, Nishida J, Tamemoto H, Fudaka K, Namai K, Kajio H, Masatoshi K, Kanazawa Y, Kawakami M. Thiazolidinediones increase the number of platelets in immune thrombocytopenic purpura mice via inhibition of phagocytic activity of the reticulo-endothelial system. Life Sci 2002 Sep 13;71(17):2037-52
[65] Breidert T, Callebert J, Heneka MT, Landreth G, Launay JM, Hirsch EC. Protective action of the peroxisome proliferator-activated receptor-gamma agonist pioglitazone in a mouse model of Parkinson's disease.. J Neurochem 2002 Aug;82(3):615-24
[66] Rumi MA, Sato H, Ishihara S, Ortega C, Kadowaki Y, Kinoshita Y. Growth inhibition of esophageal squamous carcinoma cells by peroxisome proliferator-activated receptor-gamma ligands. J Lab Clin Med 2002 Jul;140(1):17-26
[67] Nishida K, Furumatsu T, Takada I, Kawai A, Yoshida A, Kunisada T, Inoue H..Inhibition of human chondrosarcoma cell growth via apoptosis by peroxisome proliferator-activated
receptor-gamma. Br J Cancer 2002 Apr 22;86(8): 1303-9
[68] Satoh T, Toyoda M, Hoshino H, Monden T, Yamada M, Shimizu H, Miyamoto K, Mori M. Activation of peroxisome proliferator-activated receptor-gamma stimulates the growth arrest and DNA-damage inducible 153 gene in non-small cell lung carcinoma cells. Oncogene 2002 Mar 28;21(14):2171-80
[69] Goke R, Goke A, Goke B, El-Deity WS, Chen Y.Pioglitazone inhibits growth of carcinoid cells and promotes TRAIL-induced apoptosis by induction of p21 waf1/cip1. Digestion 2001;64(2):75-80
[70] Rumi MA, Sato H, Ishihara S, Kawashima K, Hamamoto S, Kazumori H, Okuyama T, Fukuda R, Nagasue N, Kinoshita Y. Peroxisome proliferator-activated receptor gamma ligand-induced growth inhibition of human hepatocellular carcinoma.. Br J Cancer 2001 Jun 15;84(12): 1640-7
[71] Weber KT, Brilla CG. Pathological hypertrophy and cardiac interstitium : fibrosis and renin-angiotensin aldosterone system. Circulation. 1991; 83:1849-1860
[72] 苏海，龙怡道，杨育红，王素英，李珊，李新立．高血压肥厚心肌纤维化及逆转。中国高血压杂志。1994；2(Suppl)：8-10
[73] Ferrannini E,Buzzigoli G, Bonodonna R, Miyazaki Y, Mahankali A, Matsuda M, Glass L, Mahankali S,Cusi K, Mandarino LJ, DeFronzo RA.Insulin resistance in essential hypertension[J]. N Engl J Med, 1987,317:350-357
[74] Stumvoll M,Haring HU. Glitazones: clinical effects and molecular mechanisms[J].Ann Med,2002;34(3):217-24.
[75] Moreau P, Takase H, Kung CF, Barton M, Vos I, Shaw S, Boer P, D'Uscio LV, Grone HJ, Rabelink TJ. Effect of chronic inhibition of nitric oxide synthesis on vascular structure: remodeling or growth? Arch Mal Coeur Vaiss. 1995;88:1141-3.
[76] Simko F, Simko J.The potential role of nitric oxide in the hypertrophic growth of the left ventricle. Physiol Res. 2000; 49(1): 37-46.
[77] Farivar RS, Chobanian AV, Brecher P. Salicylate or aspirin inhibits the induction of the inducible nitric oxide synthase in rat cardiac fibroblasts. Circ Res. 1996; 78:759-768.
[78] Takizawa T, Gu M, Chobanian AV, Kamata A, Yamamoto M, Arishima K. Effect of nitric oxide on DNA replication induced by angiotensin Ⅱ in rat cardiac fibroblasts. Hypertension. 1997; 30:1035-1040.
[79] Kim NN, Villegas S, Summerour SR, Traish AM, Kim NN, Huang YH, Min K, Munarriz R, Goldstein I. Regulation of cardiac fibroblast extracellular matrix production by bradykinin and nitric oxide. J Mol Cell Cardiol. 1999 ;31:457-466.
[80] Wang D, Yu X, Brecher P. Nitric oxide and N-acetylcysteine inhibit the activation of mitogen-activated protein kinases by angiotensin Ⅱ in rat cardiac fibroblasts. J Biol Chem 1998;273:33027-33034.
[81] Gu MF, Brecher P. Nitric oxide-induced increase in p~(21sdi1/cip1/waf1) expression during the cell cycle in aortic adventitial fibroblasts. Arterioscler Thromb Vasc Biol. 2000;20:27-34.
[82] Owens MW, Milligan SA, Jourd'heuil D, Miles AM, Johnson GG, Fields JZ, Ing TS, KottapalliV, Keshavarzian A, Grisham MB.Effects of reactive metabolites of oxygen and nitrogen on gelatinase A activity. Am J Physiol. 1997; 273: L445-L450.
[83] Chatziantoniou C, Pauti MD, Pinet F.Regulation of renin release is impaired after nitric oxide inhibition. Kidney Int. 1996,49:626-633.
[84] 余静，王永铭，辛楠，胡文兰，梁元宏，王芳．高血压患者血
浆和淋巴细胞中血管紧张素Ⅱ、内皮素和一氧化氮的变化及关系．高血压杂志。1997；5：282-284
[85] 鄢定红，程晓曙，王雪梅，张润香，李菊香，苏海，吴清华．一氧化氮缺乏在高血压及心血管重构中的作用。高血压杂志。2000；8：
[86] Usui M, Ichiki T, Katoh M, Kamata K, Inazu M, Takeda H, Goto H, Matsumiya T.Regulation of angiotensin Ⅱ receptor expression by nitric oxide in rat adrenal gland. Hypertension 1998;32:527-533.
[87] Carver W, Nagpal ML,Nachtigal M, Cpion HC, Georgakopoulos D, Takimoto E, Isoda T, Wang Y,Kass DA.Collagen expression in mechanically stimulated cardiac fibroblasts. Circ Res. 1991; 69: 116-122.
[88] Ortiz PA, Garvin JL. NO inhibit NaCl absorption by rat thick ascending limb through activation of cGMP-stimulated phosphodiesterase. Hypertension. 2001;37:467-471
[89] Lijnen PJ, Petrov VV, Fagard RH. Induction of cardiac fibrosis by transforming growth factor-beta. Mol Genet Metab. 2000;71:418-435
[90] Jacobs M, Staufenberger S, Gergs U, Paolocci N, Biondi R, Bettini M, Lee CI, Berlowitz CO, Rossi R, Xia Y, L'Abbate A, Kass DA, Zweier JL. Tumor necrosis factor-α at acute myocardial infarction in rats and effects on cardial fibroblasts. J Mol Cell Cardiol, 1999,31:1949-1959
[91] Abdelaziz N, Colombo F, Mercier I, Wedgwood S, McMullan DM, Bekker JM, Fineman JR, Black SM. Nitric oxide attenuates the expression of transforming growth factor-beta mRNA in rat cardiac fibroblasts via destabilization. Hypertension 2001 ;38:261-266
[92] Vodovotz Y, Kwon NS, Pospischil M, Kim TA, Avraham HK, Koh YH, Jiang S, Park IW, Avraham S. Inactivation of nitric oxide
synthase after prolonged incubation of mouse macrophages with IFN-gamma and bacterial lipopolysaccharide. J Immunol. 1994;152:4110-4118
[93] 赵连友，李宏伟，李雪，康建华，乔怀宇，杨学东．动脉平滑肌细胞诱导型一氧化氮合酶与高血压发病的关系[J]．中华内科杂志，2000；39(3)：168
[94] 于心亚，赵连友，郑强荪，田建伟，尚福军，李爱国，张海涛，王斌．盐酸吡格列酮对SHR心脏成纤维细胞增殖的影响及其与一氧化氮的关系[J]高血压杂志，2003，11(6)：595-598．
[2] 李光伟．高血压与糖尿病-代谢综合症的两柄利剑[J]．高血压杂志，2003，(11)1：3-4．
[3] 孙凯，张红叶，田秀珍，池丽珠，任福秀，王颖玲，黄晓红．高血压大家系中胰岛素抵抗与高血压关系的研究[J]．高血压杂志，2003，11(1)：54-57．
[4] 李光伟，杨文英，洪靖，李春梅，孙淑湘，蔡慧，王金平．胰岛素抵抗—遗传和环境因素致高血压的共同途径?[J]．中华内科杂志，2003，42(1)：11-15．
[5] 包玉倩，贾伟平，陆俊茜，陈莹，项坤三．中国人高血压个体胰岛素抵抗的影响因素[J]．中华心血管病杂志，2002，30(8)：483-486．
[6] Nash DT. Insulin Resistance, ADMA level, and Cardiovascular Disease[J]. JAMA,2002,287(11): 1451-1452.
[7] Zimmet PZ,McCarty DJ,de-Courten-MP, Reaven GM, Kaplan NM.The global epidemiology of non-insulin-dependent diabetes mellitus and the metabolic syndrome. J-Diabetes-Complications 1997,11(2):60
[8] David JG, Carol RD,Deborah S, Sugiyama Y, Ikeda H.Liver Enzyme Monitoring in Pations Treated with Troglitazone. JAMA2001 ;286:831-833.
[9] Hanefeld M, Belcher G. Safety profile of pioglitazone. Int J Clin Pract Suppl 2001 Sep;(121):27-31
[10] Henriksson F. Applications of economic models in healthcare: the introduction of pioglitazone in Sweden. Pharmacoeconomics 2002;20 Suppl 1:43-53
[11] Coyle D, Palmer AJ, Tam R. Economic evaluation of
pioglitazone, hydrochloride in the management of type 2 diabetes mellitus in Canada. Pharmacoeconomics 2002;20 Suppl 1:31-42
[12] Isseman I,Green S. Activation of a member of the steroid hormone receptor superfamily by Peroxisome Proliferators.Nature 1990,347:645-650
[13] Tugwood J, Isseman I,Green S. Sugiyama Y, Ikeda H.The mouse Peroxisome Proliferator-Activated Receptor recognize a response element in the flanking of the rat acry-CoA oxidese gene. EMBO J,1992,11:433-439
[14] Baba S. Pioglitazone: a review of Japanese clinical studies: ACTOS Clinical Studies in Japan. Curr Med Res Opin 2001;17(3):166-89
[15] Hanefeld M. Pharmacokinetics and clinical efficacy of pioglitazone. Int J Clin Pract Suppl 2001 Sep;(121):19-25
[16] Lebovitz HE. Differentiating members of the thiazolidinedione class: a focus on safety. Diabetes Metab Res Rev 2002 Mar-Apr;18 Suppl 2:S23-9
[17] Suzuki M, Odaka H, Suzuki N, Sugiyama Y, Ikeda H. Effects of combined pioglitazone and metformin on diabetes and obesity in Wistar fatty rats. Clin Exp Pharmacol Physiol 2002 Apr;29(4):269-74
[18] Goldstein BJ. Differentiating members of the thiazolidinedione class: a focus on efficacy. Diabetes Metab Res Rev 2002 Mar-Apr;18 Suppl 2:S16-22
[19] Einhorn D, Rendell M, Rosenzweig J, Egan JW, Mathisen AL, Schneider RL. Pioglitazone hydrochloride in combination with metformin in the treatment of type 2 diabetes mellitus: a randomized, placebo-controlled study。The Pioglitazone 027 Study Group. Clin Ther 2000 Dec;22(12):1395-409
[20] King AB, Armstrong DU. Lipid response to pioglitazone in diabetic patients: clinical observations from a retrospective chart review. Diabetes Teclmol Ther 2002;4(2):145-51
[21] Miyazaki Y, Mahankali A, Matsuda M, Mahankali S, Hardies J, Cusi K, Mandadno LJ, DeFronzo RA. Effect of pioglitazone on abdominal fat distribution and insulin sensitivity in type 2 diabetic patients. J Clin Endocrinol Metab 2002 Jun; 87(6): 2784-91
[22] Boyle PJ, King AB, Olansky L, Marchetti A, Lau H, Magar R, Martin J. Effects of pioglitazone and rosiglitazone on blood lipid levels and glycemic control in patients with type 2 diabetes mellitus: a retrospective review of randomly selected medical records. Clin Ther 2002 Mar;24(3):378-96
[23] Khan MA, St Peter JV, Xue JL. A prospective, randomized comparison of the metabolic effects of pioglitazone or rosiglitazone in patients with type 2 diabetes who were previously treated with troglitazone. Diabetes Care 2002 Apr;25(4):708-11
[24] Hirose H, Kawai T, Yamamoto Y, Taniyama M, Tomita M, Matsubara K, Okazaki Y, Ishii T, Oguma Y, Takei I, Saruta T. Effects of pioglitazone on metabolic parameters, body fat distribution, and serum adiponectin levels in Japanese male patients with type 2 diabetes. Metabolism 2002 Mar;51(3):314-7
[25] Tan MH.Current treatment of insulin resistance in type 2 diabetes mellitus. Int J Clin Pratt Suppl 2000 Oct;(113):54-62
[26] Smith U. Pioglitazone: mechanism of action. Int J Clin Pract Suppl 2001 Sep;(121):13-8
[27] Smith U, Gogg S, Johansson A, Olausson T, Rotter V, Svalstedt B. Thiazolidinediones (PPARgamma agonists) but not PPARalpha agonists increase IRS-2 gene expression in 3T3-L1 and human
adipocytes. FASEB J 2001 Jan;15(1):215-220.
[28] Qi N, Kazdova L, Zidek V, Landa V, Kren V, Pershadsingh HA, St Lezin E, Abumrad NA, Pravenec M, Kurtz TW.Pharmacogenetic evidence that Cd36 is a key determinant of the metabolic effects of pioglitazone.J Biol Chem 2002 Oct 15;
[29] Suzuki M, Odaka H, Suzuki N, Sugiyama Y, Ikeda H. Effects of combined pioglitazone and metformin on diabetes and obesity in Wistar fatty rats. Clin Exp Pharmacol Physiol 2002 Apr; 29(4):269-74.
[30] Keiji Yamamoto,Ruri Ohki,Richard T.Lee,Taniyama M, Tomita M, Matsubara K, Okazaki Y, Ishii T, Oguma Y, Takei I, Saruta T. Peroxisome Proliferator-Activated Receptor γ Activators inhibit cardiac hypertrophy in cardiac myocytes.Circulation 2001; 104 (14):1670—1675
[31] Sakai S, Miyauchi T, Irukayama-Tomobe Y, Ogata T, Goto K, Yamaguchi I.Peroxisome proliferator-activated receptor-gamma activators inhibit endothelin-1-related cardiac hypertrophy in rats. Clin Sci (Lond) 2002 Sep 1;103 Suppl 1:16S-20S
[32] Masayuki A,Hiroyuki T, Toshio N,Hiroki U,Hiroshi H,Naoto K, Toshihiro S,Issei K. Peroxisome Proliferator-Activated Receptor γ Plays a Critical Role in Inhibition of cardiac hypertrophy in Vitro and inVivo. Circulation 2002; 105: 1240-1246.
[33] Igarashi M, Hirata A, Yamaguchi H, Tsuchiya H, Ohnuma H, Tominaga M, Daimon M, Kato T. Characterization of an inhibitory effect of pioglitazone on balloon-injured vascular smooth muscle cell growth.. Metabolism 2001 Aug;50(8):955-62)
[34] Aizawa Y, Kawabe J, Hasebe N, Takehara N, Kikuchi K. Pioglitazone enhances cytokine-induced apoptosis in vascular smooth
muscle cells and reduces intimal hyperplasia.. Circulation 2001 Jul 24;104(4):455-60)
[35] Ishibashi M, Egashira K, Hiasa K, Inoue S, Ni W, Zhao Q, Usui M, Kitamoto S, Ichiki T, Takeshita A. Antiinflammatory and antiarteriosclerotic effects of pioglitazone.. Hypertension 2002 Nov;40(5):687-93)
[36] Tian-li Yue,PhD;Jun Chen, MS;Weike Bao,MD;Padma KN,PhD; Antoine B,PhD;Wen Jiang,MD;Paul GL,MD,In Vivo Myocardial Protection From Ischemia/Reperfusion Injury by the Peroxisome Proliferator-Activated Receptor γ Agonist Rosiglitazone. Circulation 2001; 104: 2588-2594。
[37] 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. Lab Invest. 2003 Dec;83(12):1715-21.
[38] Wayman NS, Hattori Y, McDonald MC, Mota-Filipe H, Cuzzocrea S, Pisano B, Chatterjee PK, Thiemermann C. Ligands of the peroxisome proliferator-activated receptors (PPAR-gamma and PPAR-alpha) reduce myocardial infarct size. FASEB J 2002 Jul; 16(9): 1027-40。
[39] 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 May;51(5):1507-14
[40] Delerive P, Fruchart JC, Staels B. Faveeuw C, Fougeray S, Angeli V, Fontaine J, Chinetti G, Gosset P,Maliszewski C, Capron M, Moser M, Trottein F..Peroxisome proliferator-activated receptors in
inflammation control. J Endocrinol 2001 Jun;169(3):453.
[41] Cemuda-Morollon E, Rodriguez-Pascual F, Klatt P, Lamas S, Perez-Sala D. PPAR Agonists Amplify iNOS Expression While Inhibiting NF-kappaB: Implications for Mesangial Cell Activation by Cytokines. J Am Soc Nephrol. 2002 Sep; 13(9):2223-31。
[42] Haffner SM, Greenberg AS, Weston WM,Chen H,Williams K, Freed MI. Effect of rosiglitazone treatment on nontraditional markers of cardiovascular disease in patients with type 2 diabetes mellitus. Circulation 2002 Aug 6;106(6):679-84
[43] Nikolaus Marx, Bettina Kehrle, Klaus Kohlhammer, Miriam Grub,Wolfgang Koenig,Vinzenz Hombach,Peter Libby, Jorge Plutzky. PPAR Activators as Antiinflammatory Mediators in Human T Lymphocytes. Circ Res.2002;90:703-710.
[44] Stuhlinger MC,Abbasi F, Chu JW.Lamendola C,McLaughlin TL,Cooke JP, Reaven GM,Tsao PS.Relationship Between Insulin Resistance and an Endogenous Nitric Oxide Synthese Inhibitor. JAMA2002, 287(11): 1420—1426
[45] Dobrian AD, Schriver SD, Khraibi AA, Prewitt RL.Pioglitazone prevents hypertension and reduces oxidative stress in diet-induced obesity. Hypertension. 2004 Jan;43(1):48-56. Epub 2003 Nov 24.
[46] Fullert S, Schneider F, Haak E, Rau H, Badenhoop K, Lubben G, Usadel KH, Konrad T. Effects of pioglitazone in nondiabetic patients with arterial hypertension: a double-blind, placebo-controlled study. J Clin Endocrinol Metab. 2002 Dec;87(12):5503-6.
[47] Gerber P, Lubben G, Heusler S, Dodo A. Effects of pioglitazone on metabolic control and blood pressure: a randomised study in patients with type 2 diabetes mellitus. Curr Med Res Opin. 2003;19(6):532-9.
[48] Roberts AW, Thomas A,Rees A,Evans M.Peroxisome proliferator-activated receptor-gamma agonists in atherosclerosis: current evidence and future directions. Curr Opin Lipidol. 2003 Dec;14(6):567-73.
[49] Tsuji T, Mizushige K, Noma T, Murakami K, Ohmori K, Miyatake A, Kohno M. Pioglitazone improves left ventricular diastolic function and decreases collagen accumulation in prediabetic stage of a type Ⅱ diabetic rat. J Cardiovasc Pharmacol 2001 Dec;38(6):868-74.
[50] Kim SK, Zhao ZS, Lee YJ, Lee KE, Kang SM, Choi D, Lim SK, Chung N, Lee HC, Cha BS. Left-ventricular diastolic dysfunction may be prevented by chronic treatment with PPAR-alpha or -gamma agonists in a type 2 diabetic animal model. Diabetes Metab Res Rev. 2003 Nov-Dee; 19(6):487-93.
[51] Winkler K, Konrad T, Fullert S, Friedrich I, Destani R, Baumstark MW, Krebs K, Wieland H, Marz W. Pioglitazone reduces atherogenic dense LDL particles in nondiabetic patients with arterial hypertension: a double-blind, placebo-controlled study.Diabetes Care. 2003 Sep;26(9):2588-94.
[52] Stumvoll M, Hating HU. Glitazones: clinical effects and molecular mechanisms. Ann Med 2002;34(3):217-24
[53] Meier C, Chicheportiche R, Juge-Aubry C, Dreyer M, Dayer J. Regulation of the interleukin-1 receptor antagonist in THP-1 cells by ligands of the peroxisome proliferator-activated receptor gamma.. Cytokine 2002 Jun 21;18(6):320
[54] Shiojiri T, Wada K, Nakajima A, Katayama K, Shibuya A, Kudo C, Kadowaki T, Mayumi T, Yura Y, Kamisaki Y. PPARgamma ligands inhibit, nitrotyrosine formation and inflammatory mediator expressions in adjuvant-induced rheumatoid arthritis mice..Eur J
Pharmacol 2002 Jul 19;448(2-3):231-8
[55] Iida KT, Kawakami Y, Suzuki H, Sone H, Shimano H, Toyoshima H, Okuda Y, Yamada N. PPAR gamma ligands, troglitazone and pioglitazone, up-regulate expression of HMG-CoA synthase and HMG-CoA reductase gene in THP-1 macrophages. FEBS Lett 2002 Jun 5;520(1-3):177-81
[56] Galli A, Crabb DW, Ceni E, Salzano R, Mello T, Svegliati-Baroni G, Ridolfi F, Trozzi L, Surrenti C, Casini A. Antidiabetic thiazolidinediones inhibit collagen synthesis and hepatic stellate cell activation in vivo and in vitro. Gastroenterology 2002 Jun; 122(7): 1924-40
[57] Kon K, Ikejima K, Hirose M, Yoshikawa M, Enomoto N, Kitamura T, Takei Y, Sato N. Yoshikawa M, Enomoto N, Kitamura T, Takei Y, Sato N.Pioglitazone prevents early-phase hepatic fibrogenesis caused by carbon tetrachloride. Biochem Biophys Res Commun 2002 Feb 15;291(1):55-61.
[58] Kawaguchi K, Sakaida I, Tsuchiya M, Omori K, Takami T, Okita K. Pioglitazone prevents hepatic steatosis, fibrosis, and enzyme-altered lesions in rat liver cirrhosis induced by a choline-deficient L-amino acid-defined diet. Biochem Biophys Res Commun. 2004 Feb 27;315(1):187-95.
[59] Kawakami S, Arai G, Hayashi T, Fujii Y, Xia G; Kageyama Y, Kihara K. PPARgamma ligands suppress proliferation of human urothelial basal cells in vitro. J Cell Physiol 2002 Jun;191(3):310-9
[60] Nakamuta M, Enjoji M, Uchimura K, Ohta S, Sugimoto R, Kotoh K, Kato M, Irie T, Muta T, Nawata H. Bisphenol A diglycidyl ether (BADGE)supprwsses tumor necrosis factor-α(TNF-α)production as a PPARgamma agonist in the murine macrophage-like cell line
RAW 264.7. Cell Biol Int 2002;26(3):235-41
[61] Nakamura T, Ushiyama C, Osada S, Hara M, Shimada N, Koide H. Pioglitazone reduces urinary podocyte excretion in type 2 diabetes patients with microalbuminuria.Metabolism 2001 Oct;50(10): 1193-6
[62] Yanagawa T, Araki A, Sasamoto K, Shirabe S, Yamanouchi T. Effect of antidiabetic medications on microalbuminuria in patients with type 2 diabetes. Metabolism. 2004 Mar;53(3):353-7.
[63] Feinstein DL, Galea E, Gavrilyuk V, Brosnan CF, Whitacre CC, Dumitrescu-Ozimek L, Landreth GE, Pershadsingh HA, Weinberg G, Heneka MT. Peroxisome proliferator-activated receptor-gamma agonists prevent experimental autoimmune encephalomyelitis,。Ann Neurol 2002 Jun;51(6):694-702
[64] Kasono K, Nishida J, Tamemoto H, Fudaka K, Namai K, Kajio H, Masatoshi K, Kanazawa Y, Kawakami M. Thiazolidinediones increase the number of platelets in immune thrombocytopenic purpura mice via inhibition of phagocytic activity of the reticulo-endothelial system. Life Sci 2002 Sep 13;71(17):2037-52
[65] Breidert T, Callebert J, Heneka MT, Landreth G, Launay JM, Hirsch EC. Protective action of the peroxisome proliferator-activated receptor-gamma agonist pioglitazone in a mouse model of Parkinson's disease.. J Neurochem 2002 Aug;82(3):615-24
[66] Rumi MA, Sato H, Ishihara S, Ortega C, Kadowaki Y, Kinoshita Y. Growth inhibition of esophageal squamous carcinoma cells by peroxisome proliferator-activated receptor-gamma ligands. J Lab Clin Med 2002 Jul;140(1):17-26
[67] Nishida K, Furumatsu T, Takada I, Kawai A, Yoshida A, Kunisada T, Inoue H..Inhibition of human chondrosarcoma cell growth via apoptosis by peroxisome proliferator-activated
receptor-gamma. Br J Cancer 2002 Apr 22;86(8): 1303-9
[68] Satoh T, Toyoda M, Hoshino H, Monden T, Yamada M, Shimizu H, Miyamoto K, Mori M. Activation of peroxisome proliferator-activated receptor-gamma stimulates the growth arrest and DNA-damage inducible 153 gene in non-small cell lung carcinoma cells. Oncogene 2002 Mar 28;21(14):2171-80
[69] Goke R, Goke A, Goke B, El-Deity WS, Chen Y.Pioglitazone inhibits growth of carcinoid cells and promotes TRAIL-induced apoptosis by induction of p21 waf1/cip1. Digestion 2001;64(2):75-80
[70] Rumi MA, Sato H, Ishihara S, Kawashima K, Hamamoto S, Kazumori H, Okuyama T, Fukuda R, Nagasue N, Kinoshita Y. Peroxisome proliferator-activated receptor gamma ligand-induced growth inhibition of human hepatocellular carcinoma.. Br J Cancer 2001 Jun 15;84(12): 1640-7
[71] Weber KT, Brilla CG. Pathological hypertrophy and cardiac interstitium : fibrosis and renin-angiotensin aldosterone system. Circulation. 1991; 83:1849-1860
[72] 苏海，龙怡道，杨育红，王素英，李珊，李新立．高血压肥厚心肌纤维化及逆转。中国高血压杂志。1994；2(Suppl)：8-10
[73] Ferrannini E,Buzzigoli G, Bonodonna R, Miyazaki Y, Mahankali A, Matsuda M, Glass L, Mahankali S,Cusi K, Mandarino LJ, DeFronzo RA.Insulin resistance in essential hypertension[J]. N Engl J Med, 1987,317:350-357
[74] Stumvoll M,Haring HU. Glitazones: clinical effects and molecular mechanisms[J].Ann Med,2002;34(3):217-24.
[75] Moreau P, Takase H, Kung CF, Barton M, Vos I, Shaw S, Boer P, D'Uscio LV, Grone HJ, Rabelink TJ. Effect of chronic inhibition of nitric oxide synthesis on vascular structure: remodeling or growth? Arch Mal Coeur Vaiss. 1995;88:1141-3.
[76] Simko F, Simko J.The potential role of nitric oxide in the hypertrophic growth of the left ventricle. Physiol Res. 2000; 49(1): 37-46.
[77] Farivar RS, Chobanian AV, Brecher P. Salicylate or aspirin inhibits the induction of the inducible nitric oxide synthase in rat cardiac fibroblasts. Circ Res. 1996; 78:759-768.
[78] Takizawa T, Gu M, Chobanian AV, Kamata A, Yamamoto M, Arishima K. Effect of nitric oxide on DNA replication induced by angiotensin Ⅱ in rat cardiac fibroblasts. Hypertension. 1997; 30:1035-1040.
[79] Kim NN, Villegas S, Summerour SR, Traish AM, Kim NN, Huang YH, Min K, Munarriz R, Goldstein I. Regulation of cardiac fibroblast extracellular matrix production by bradykinin and nitric oxide. J Mol Cell Cardiol. 1999 ;31:457-466.
[80] Wang D, Yu X, Brecher P. Nitric oxide and N-acetylcysteine inhibit the activation of mitogen-activated protein kinases by angiotensin Ⅱ in rat cardiac fibroblasts. J Biol Chem 1998;273:33027-33034.
[81] Gu MF, Brecher P. Nitric oxide-induced increase in p~(21sdi1/cip1/waf1) expression during the cell cycle in aortic adventitial fibroblasts. Arterioscler Thromb Vasc Biol. 2000;20:27-34.
[82] Owens MW, Milligan SA, Jourd'heuil D, Miles AM, Johnson GG, Fields JZ, Ing TS, KottapalliV, Keshavarzian A, Grisham MB.Effects of reactive metabolites of oxygen and nitrogen on gelatinase A activity. Am J Physiol. 1997; 273: L445-L450.
[83] Chatziantoniou C, Pauti MD, Pinet F.Regulation of renin release is impaired after nitric oxide inhibition. Kidney Int. 1996,49:626-633.
[84] 余静，王永铭，辛楠，胡文兰，梁元宏，王芳．高血压患者血
浆和淋巴细胞中血管紧张素Ⅱ、内皮素和一氧化氮的变化及关系．高血压杂志。1997；5：282-284
[85] 鄢定红，程晓曙，王雪梅，张润香，李菊香，苏海，吴清华．一氧化氮缺乏在高血压及心血管重构中的作用。高血压杂志。2000；8：
[86] Usui M, Ichiki T, Katoh M, Kamata K, Inazu M, Takeda H, Goto H, Matsumiya T.Regulation of angiotensin Ⅱ receptor expression by nitric oxide in rat adrenal gland. Hypertension 1998;32:527-533.
[87] Carver W, Nagpal ML,Nachtigal M, Cpion HC, Georgakopoulos D, Takimoto E, Isoda T, Wang Y,Kass DA.Collagen expression in mechanically stimulated cardiac fibroblasts. Circ Res. 1991; 69: 116-122.
[88] Ortiz PA, Garvin JL. NO inhibit NaCl absorption by rat thick ascending limb through activation of cGMP-stimulated phosphodiesterase. Hypertension. 2001;37:467-471
[89] Lijnen PJ, Petrov VV, Fagard RH. Induction of cardiac fibrosis by transforming growth factor-beta. Mol Genet Metab. 2000;71:418-435
[90] Jacobs M, Staufenberger S, Gergs U, Paolocci N, Biondi R, Bettini M, Lee CI, Berlowitz CO, Rossi R, Xia Y, L'Abbate A, Kass DA, Zweier JL. Tumor necrosis factor-α at acute myocardial infarction in rats and effects on cardial fibroblasts. J Mol Cell Cardiol, 1999,31:1949-1959
[91] Abdelaziz N, Colombo F, Mercier I, Wedgwood S, McMullan DM, Bekker JM, Fineman JR, Black SM. Nitric oxide attenuates the expression of transforming growth factor-beta mRNA in rat cardiac fibroblasts via destabilization. Hypertension 2001 ;38:261-266
[92] Vodovotz Y, Kwon NS, Pospischil M, Kim TA, Avraham HK, Koh YH, Jiang S, Park IW, Avraham S. Inactivation of nitric oxide
synthase after prolonged incubation of mouse macrophages with IFN-gamma and bacterial lipopolysaccharide. J Immunol. 1994;152:4110-4118
[93] 赵连友，李宏伟，李雪，康建华，乔怀宇，杨学东．动脉平滑肌细胞诱导型一氧化氮合酶与高血压发病的关系[J]．中华内科杂志，2000；39(3)：168
[94] 于心亚，赵连友，郑强荪，田建伟，尚福军，李爱国，张海涛，王斌．盐酸吡格列酮对SHR心脏成纤维细胞增殖的影响及其与一氧化氮的关系[J]高血压杂志，2003，11(6)：595-598．