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系統識別號 U0026-2307201418480700
論文名稱(中文) 探討Thiazolidinedione引發血漿體積擴張及心臟肥大的角色
論文名稱(英文) Study of Thiazolidinedione-Induced Plasma Volume Expansion and Cardiac Hypertrophy
校院名稱 成功大學
系所名稱(中) 基礎醫學研究所
系所名稱(英) Institute of Basic Medical Sciences
學年度 102
學期 2
出版年 103
研究生(中文) 張程翔
研究生(英文) Cherng-Shyang Chang
學號 S58961086
學位類別 博士
語文別 英文
論文頁數 110頁
口試委員 指導教授-蔡佩珍
召集委員-賴明德
口試委員-蔡美玲
口試委員-蔡曜聲
口試委員-林天南
口試委員-洪麗滿
中文關鍵字 加馬型過氧化體增殖活化受體  噻唑烷二酮  血漿體積擴張  心臟肥大  利尿劑 
英文關鍵字 PPARγ  thiazolidinediones  plasma volume expansion  cardiac hypertrophy  diuretics 
學科別分類
中文摘要 加馬型過氧化體增殖活化受體 (Peroxisome proliferator-activated receptor γ, PPARγ)是重要的轉錄調節因子,在多種組織及細胞中負責調控代謝機制。因此在臨床中,PPARγ的促效劑噻唑烷二酮(Thiazolidinedione, TZD)類藥物像是羅格列酮(rosiglitazone, Rosi)和匹格列酮(pioglitazone, Pio),即用於治療第二型糖尿病相關的胰島素阻抗。然而許多關於TZD類藥物對心臟副作用的報導,確實造成用藥上的疑慮。雖然TZD類藥物引發的心臟肥大推測是由於血漿體積擴張所導致,但直接的證據並未被建立。此外,PPARγ影響心臟的代謝也可能是TZD引發的心臟肥大的原因。為驗證我們的假設,即TZD引發的心臟肥大是血漿體積增加所導致,我們將小鼠餵與高脂肪飲食以及TZD並觀察心臟和代謝的變化。我們發現Rosi使得野生型小鼠以及單套PPARγ基因剃除(Pparg+/-)小鼠出現血漿體積擴張和心臟肥大,但這些現象卻不在PPARγ基因受體接位缺乏(PpargP465L/+)的小鼠中出現。野生型小鼠同時若給予利尿劑furosemide治療,能夠有效減低Rosi所引發的血漿體積擴張、心臟肥大、心臟肥大基因的啟動、心肌凋亡、心臟肥大訊息活化及左心室功能缺失。有趣的是,心臟的葡萄糖及脂肪代謝基因會受到Rosi影響,但這個影響卻並未隨著利尿劑的給予而減低。類似的結果也在Pio治療的小鼠中觀察到。其他種類利尿劑像是spironolactone以及tricholormethiazide一樣能減低Rosi造成的血漿體積擴張和心臟肥大,但利尿劑amiloride 則無法改善上述症狀。更重要的是在同時給予利尿劑治療時,TZD對於全身代謝的改善現象並不受到干擾。總結本研究,我們證實利用利尿劑釋放血漿體積能有效減低TZD引發血漿體積擴張及心臟肥大等副作用,並且不會干擾TZD類藥物在心臟代謝或是全身胰島素敏感性的影響。這可作為一個立即應用的治療策略,而不需要將TZD從市場下架,或是等待新的PPARγ標靶藥物測試。
英文摘要 Peroxisome proliferator-activated receptor γ (PPARγ) is a critical transcription factor mediating metabolism in diverse tissues or cells. The PPARγ agonist thiazolidinediones (TZDs), including rosiglitazone (Rosi) and pioglitazone (Pio), are used clinically to treat type 2 diabetes. However, much concern of TZDs has arisen regarding critical side effects on heart. Although TZD-induced cardiac hypertrophy has been attributed to an increase in plasma volume or a change in cardiac nutrient preference, the true causative roles have not yet been established. To test the hypothesis that plasma volume expansion directly mediates Rosi-induced cardiac hypertrophy, mice were fed a high-fat diet with Rosi and cardiac and metabolic consequences were examined. Rosi treatment induced plasma volume expansion and cardiac hypertrophy in wild-type and PPARγ heterozygous knockout (Pparg+/-) mice, but not in a mutant strain of mice defective for ligand binding (PpargP465L/+). Co-treatment with the diuretic furosemide (Furo) in wild-type mice attenuated Rosi-induced plasma volume expansion, cardiac hypertrophy, hypertrophic gene reprogramming, cardiomyocyte apoptosis, hypertrophy-related signal activation, and left ventricular dysfunction. Interestingly, glucose and lipid metabolism genes in the heart were altered by Rosi, while these changes were not attenuated by Furo co-treatment. Similar changes were also observed when mice were treated with Pio. Other diuretics, including spironolactone and tricholormethiazide, but not amiloride, attenuated Rosi effects on plasma volume expansion and cardiac hypertrophy. Importantly, Rosi-mediated whole-body metabolic improvements were not affected by Furo co-treatment. Together, we evidenced that releasing plasma volume by diuretics lowers side effects of TZD-induced plasma volume expansion and cardiac events without compromising TZD’s actions in metabolic switch in the heart and whole-body insulin sensitivity. This is a strategy that could be immediately adopted without withdrawal of TZDs and testing new drugs that target PPARγ.
論文目次 Abstract.......I
Abstract in Chinese......III
Acknowledgments ......IV
Contents ......V
Table contents .....VIII
Figure contents ......IX
Abbreviations ......XI

Chapter 1: Introduction .....1
1.1 Peroxisome proliferator-activated receptor γ..1
1.2 PPARγ ligands and thiazolidinediones ...1
1.3 Cardiac hypertrophy ....2
1.4 Fetal gene reprogramming in cardiac hypertrophy.5
1.5 Metabolic gene switch and alteration of metabolism in hypertrophic heart ......7
1.6 Signaling pathway involved in development of cardiac hypertrophy ......10
1.7 PPARγ and cardiac hypertrophy ...12
1.8 Metabolic role of PPARγ in cardiac hypertrophy ..13
1.9 Sodium reabsorption and plasma volume ...13
1.10 Plasma volume expansion and TZD-induced cardiac hypertrophy ......14

Chapter 2: Objective and specific aims ...16

Chapter 3: Materials and Methods ...18
3.1 Animals .....18
3.2 Plasma volume analysis ....18
3.3 Sodium analysis .....19
3.4 Histological analysis of heart ....19
3.5 Isolation of adult mouse ventricular cardiomyocytes ........19
3.6 RNA analysis ......20
3.7 Echocardiography ....20
3.8 Western blotting ....21
3.9 Immunohistochemical staining ....21
3.10 Cell Cultures and treatments ...21
3.11 Metabolic and physiological measurements ...22
3.12 Data analysis ......22

Chapter 4: Results .....24
4.1 Rosi induces plasma volume expansion and cardiac hypertrophy through PPARγ.....24
4.2 Co-treatment with furosemide prevents Rosi-induced plasma volume expansion and cardiac hypertrophy ..25
4.3 Fetal gene reprogramming and cardiac dysfunction are induced by plasma volume expansion in Rosi-induced cardiac hypertrophy ......26
4.4 Rosi-induced cardiac hypertrophy is mediated through Erk1/2 signaling .....27
4.5 Glucose and lipid metabolic genes are not dependent on plasma volume expansion in Rosi-induced cardiac hypertrophy ........28
4.6 Rosi does not cause cardiac hypertrophy in vitro ..29
4.7 Pio-induced cardiac hypertrophy is also mediated through plasma volume expansion ....30
4.8 Rosi-induced cardiac hypertrophy is re-appeared after discontinuing Furo administration ....31
4.9 Amiloride does not prevent Rosi-induced plasma volume expansion and cardiac hypertrophy ....31
4.10 Spironolactone and TCM prevent Rosi-induced plasma volume expansion and cardiac hypertrophy ...32
4.11 Furo co-treatment does not compromise the whole-body insulin-sensitizing effects of TZD ...32

Chapter 5: Discussion ....34
5.1 Dependence of TZD-induced cardiac hypertrophy on PPARγ ........34
5.2 Dependence of TZD-induced cardiac hypertrophy on plasma volume expansion......35
5.3 Effects of TZD-induced plasma volume expansion on heart ........36
5.4 Importance of renal sodium transporters in TZD-induced plasma volume expansion and cardiac hypertrophy ..37
5.5 Associations among TZD-induced hypotension, plasma volume expansion, and cardiac hypertrophy ..38
5.6 Metabolic effects of TZDs on heart ..39
5.7 Comparisons between Rosi and Pio ....40

Chapter 6: Conclusions .....41

References .......43

Tables .......50

Figures ......56

Appendices .......81

Curriculum vitae ......110
參考文獻 1. Desvergne B, Wahli W: Peroxisome proliferator-activated receptors: nuclear control of metabolism, Endocr Rev 1999, 20:649-688
2. Willson TM, Lambert MH, Kliewer SA: Peroxisome proliferator-activated receptor gamma and metabolic disease, Annu Rev Biochem 2001, 70:341-367
3. Rangwala SM, Lazar MA: Peroxisome proliferator-activated receptor gamma in diabetes and metabolism, Trends Pharmacol Sci 2004, 25:331-336
4. Bishop-Bailey D: Peroxisome proliferator-activated receptors in the cardiovascular system, Br J Pharmacol 2000, 129:823-834
5. Takano H, Komuro I: Peroxisome proliferator-activated receptor gamma and cardiovascular diseases, Circ J 2009, 73:214-220
6. Viswakarma N, Jia Y, Bai L, Vluggens A, Borensztajn J, Xu J, Reddy JK: Coactivators in PPAR-Regulated Gene Expression, PPAR Res 2010, 2010:250126
7. 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
8. Lehmann JM, Moore LB, Smith-Oliver TA, Wilkison WO, Willson TM, Kliewer SA: An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR gamma), J Biol Chem 1995, 270:12953-12956
9. Elbrecht A, Chen Y, Cullinan CA, Hayes N, Leibowitz M, Moller DE, Berger J: Molecular cloning, expression and characterization of human peroxisome proliferator activated receptors gamma 1 and gamma 2, Biochem Biophys Res Commun 1996, 224:431-437
10. Nissen SE, Wolski K: Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes, N Engl J Med 2007, 356:2457-2471
11. Arakawa K, Ishihara T, Aoto M, Inamasu M, Kitamura K, Saito A: An antidiabetic thiazolidinedione induces eccentric cardiac hypertrophy by cardiac volume overload in rats, Clin Exp Pharmacol Physiol 2004, 31:8-13
12. Pickavance LC, Tadayyon M, Widdowson PS, Buckingham RE, Wilding JP: Therapeutic index for rosiglitazone in dietary obese rats: separation of efficacy and haemodilution, Br J Pharmacol 1999, 128:1570-1576
13. Dorn GW, 2nd, Robbins J, Sugden PH: Phenotyping hypertrophy: eschew obfuscation, Circ Res 2003, 92:1171-1175
14. Barry SP, Davidson SM, Townsend PA: Molecular regulation of cardiac hypertrophy, Int J Biochem Cell Biol 2008, 40:2023-2039
15. Heineke J, Molkentin JD: Regulation of cardiac hypertrophy by intracellular signalling pathways, Nat Rev Mol Cell Biol 2006, 7:589-600
16. Garcia JA, Incerpi EK: Factors and mechanisms involved in left ventricular hypertrophy and the anti-hypertrophic role of nitric oxide, Arq Bras Cardiol 2008, 90:409-416
17. Miyata S, Minobe W, Bristow MR, Leinwand LA: Myosin heavy chain isoform expression in the failing and nonfailing human heart, Circ Res 2000, 86:386-390
18. Ruzicka DL, Schwartz RJ: Sequential activation of alpha-actin genes during avian cardiogenesis: vascular smooth muscle alpha-actin gene transcripts mark the onset of cardiomyocyte differentiation, J Cell Biol 1988, 107:2575-2586
19. Driesen RB, Verheyen FK, Debie W, Blaauw E, Babiker FA, Cornelussen RN, Ausma J, Lenders MH, Borgers M, Chaponnier C, Ramaekers FC: Re-expression of alpha skeletal actin as a marker for dedifferentiation in cardiac pathologies, J Cell Mol Med 2009, 13:896-908
20. Hewett TE, Grupp IL, Grupp G, Robbins J: Alpha-skeletal actin is associated with increased contractility in the mouse heart, Circ Res 1994, 74:740-746
21. Nishikimi T, Maeda N, Matsuoka H: The role of natriuretic peptides in cardioprotection, Cardiovasc Res 2006, 69:318-328
22. Cameron VA, Ellmers LJ: Minireview: natriuretic peptides during development of the fetal heart and circulation, Endocrinology 2003, 144:2191-2194
23. Kawakami H, Okayama H, Hamada M, Hiwada K: Alteration of atrial natriuretic peptide and brain natriuretic peptide gene expression associated with progression and regression of cardiac hypertrophy in renovascular hypertensive rats, Clin Sci (Lond) 1996, 90:197-204
24. Zhao D, Pandey KN, Navar LG: ANP-mediated inhibition of distal nephron fractional sodium reabsorption in wild-type and mice overexpressing natriuretic peptide receptor, Am J Physiol Renal Physiol 2010, 298:F103-108
25. Ganguly A: Atrial natriuretic peptide-induced inhibition of aldosterone secretion: a quest for mediator(s), Am J Physiol 1992, 263:E181-194
26. Taegtmeyer H, Sen S, Vela D: Return to the fetal gene program: a suggested metabolic link to gene expression in the heart, Ann N Y Acad Sci 2010, 1188:191-198
27. Lewin TM, Coleman RA: Regulation of myocardial triacylglycerol synthesis and metabolism, Biochim Biophys Acta 2003, 1634:63-75
28. Kolwicz SC, Jr., Tian R: Glucose metabolism and cardiac hypertrophy, Cardiovasc Res 2011, 90:194-201
29. Rajabi M, Kassiotis C, Razeghi P, Taegtmeyer H: Return to the fetal gene program protects the stressed heart: a strong hypothesis, Heart Fail Rev 2007, 12:331-343
30. Ross RS, Borg TK: Integrins and the myocardium, Circ Res 2001, 88:1112-1119
31. Frey N, Olson EN: Cardiac hypertrophy: the good, the bad, and the ugly, Annu Rev Physiol 2003, 65:45-79
32. Nicol RL, Frey N, Olson EN: From the sarcomere to the nucleus: role of genetics and signaling in structural heart disease, Annu Rev Genomics Hum Genet 2000, 1:179-223
33. Morisco C, Zebrowski DC, Vatner DE, Vatner SF, Sadoshima J: Beta-adrenergic cardiac hypertrophy is mediated primarily by the beta(1)-subtype in the rat heart, J Mol Cell Cardiol 2001, 33:561-573
34. Redfern CH, Degtyarev MY, Kwa AT, Salomonis N, Cotte N, Nanevicz T, Fidelman N, Desai K, Vranizan K, Lee EK, Coward P, Shah N, Warrington JA, Fishman GI, Bernstein D, Baker AJ, Conklin BR: Conditional expression of a Gi-coupled receptor causes ventricular conduction delay and a lethal cardiomyopathy, Proc Natl Acad Sci U S A 2000, 97:4826-4831
35. Olson EN, Schneider MD: Sizing up the heart: development redux in disease, Genes Dev 2003, 17:1937-1956
36. Domingos PP, Fonseca PM, Nadruz W, Jr., Franchini KG: Load-induced focal adhesion kinase activation in the myocardium: role of stretch and contractile activity, Am J Physiol Heart Circ Physiol 2002, 282:H556-564
37. Gordon JW, Shaw JA, Kirshenbaum LA: Multiple facets of NF-kappaB in the heart: to be or not to NF-kappaB, Circ Res 2011, 108:1122-1132
38. Asakawa M, Takano H, Nagai T, Uozumi H, Hasegawa H, Kubota N, Saito T, Masuda Y, Kadowaki T, Komuro I: Peroxisome proliferator-activated receptor gamma plays a critical role in inhibition of cardiac hypertrophy in vitro and in vivo, Circulation 2002, 105:1240-1246
39. Duan SZ, Ivashchenko CY, Russell MW, Milstone DS, Mortensen RM: Cardiomyocyte-specific knockout and agonist of peroxisome proliferator-activated receptor-gamma both induce cardiac hypertrophy in mice, Circ Res 2005, 97:372-379
40. Yamamoto K, Ohki R, Lee RT, Ikeda U, Shimada K: Peroxisome proliferator-activated receptor gamma activators inhibit cardiac hypertrophy in cardiac myocytes, Circulation 2001, 104:1670-1675
41. Bao Y, Li R, Jiang J, Cai B, Gao J, Le K, Zhang F, Chen S, Liu P: Activation of peroxisome proliferator-activated receptor gamma inhibits endothelin-1-induced cardiac hypertrophy via the calcineurin/NFAT signaling pathway, Mol Cell Biochem 2008, 317:189-196
42. Guan Y, Hao C, Cha DR, Rao R, Lu W, Kohan DE, Magnuson MA, Redha R, Zhang Y, Breyer MD: Thiazolidinediones expand body fluid volume through PPARgamma stimulation of ENaC-mediated renal salt absorption, Nat Med 2005, 11:861-866
43. Zhang H, Zhang A, Kohan DE, Nelson RD, Gonzalez FJ, Yang T: Collecting duct-specific deletion of peroxisome proliferator-activated receptor gamma blocks thiazolidinedione-induced fluid retention, Proc Natl Acad Sci U S A 2005, 102:9406-9411
44. Nathan DM: Clinical practice. Initial management of glycemia in type 2 diabetes mellitus, N Engl J Med 2002, 347:1342-1349
45. Lehman JJ, Kelly DP: Gene regulatory mechanisms governing energy metabolism during cardiac hypertrophic growth, Heart Fail Rev 2002, 7:175-185
46. Kurtz DM, Rinaldo P, Rhead WJ, Tian L, Millington DS, Vockley J, Hamm DA, Brix AE, Lindsey JR, Pinkert CA, O'Brien WE, Wood PA: Targeted disruption of mouse long-chain acyl-CoA dehydrogenase gene reveals crucial roles for fatty acid oxidation, Proc Natl Acad Sci U S A 1998, 95:15592-15597
47. Son NH, Park TS, Yamashita H, Yokoyama M, Huggins LA, Okajima K, Homma S, Szabolcs MJ, Huang LS, Goldberg IJ: Cardiomyocyte expression of PPARgamma leads to cardiac dysfunction in mice, J Clin Invest 2007, 117:2791-2801
48. Knepper MA, Brooks HL: Regulation of the sodium transporters NHE3, NKCC2 and NCC in the kidney, Curr Opin Nephrol Hypertens 2001, 10:655-659
49. Pavlov TS, Imig JD, Staruschenko A: Regulation of ENaC-Mediated Sodium Reabsorption by Peroxisome Proliferator-Activated Receptors, PPAR Res 2010, 2010:703735
50. Geering K: Functional roles of Na,K-ATPase subunits, Curr Opin Nephrol Hypertens 2008, 17:526-532
51. Biber J, Hernando N, Forster I: Phosphate transporters and their function, Annu Rev Physiol 2013, 75:535-550
52. Ali SS, Sharma PK, Garg VK, Singh AK, Mondal SC: The target-specific transporter and current status of diuretics as antihypertensive, Fundam Clin Pharmacol 2012, 26:175-179
53. Shah SU, Anjum S, Littler WA: Use of diuretics in cardiovascular disease: (2) hypertension, Postgrad Med J 2004, 80:271-276
54. Kalra PR, Anagnostopoulos C, Bolger AP, Coats AJ, Anker SD: The regulation and measurement of plasma volume in heart failure, J Am Coll Cardiol 2002, 39:1901-1908
55. Guan Y, Zhang Y, Davis L, Breyer MD: Expression of peroxisome proliferator-activated receptors in urinary tract of rabbits and humans, Am J Physiol 1997, 273:F1013-1022
56. Song J, Knepper MA, Hu X, Verbalis JG, Ecelbarger CA: Rosiglitazone activates renal sodium- and water-reabsorptive pathways and lowers blood pressure in normal rats, J Pharmacol Exp Ther 2004, 308:426-433
57. Raskin P, Rendell M, Riddle MC, Dole JF, Freed MI, Rosenstock J: A randomized trial of rosiglitazone therapy in patients with inadequately controlled insulin-treated type 2 diabetes, Diabetes Care 2001, 24:1226-1232
58. Rosenstock J, Einhorn D, Hershon K, Glazer NB, Yu S: Efficacy and safety of pioglitazone in type 2 diabetes: a randomised, placebo-controlled study in patients receiving stable insulin therapy, Int J Clin Pract 2002, 56:251-257
59. Katz AM: Cardiomyopathy of overload. A major determinant of prognosis in congestive heart failure, N Engl J Med 1990, 322:100-110
60. Fiorillo C, Nediani C, Ponziani V, Giannini L, Celli A, Nassi N, Formigli L, Perna AM, Nassi P: Cardiac volume overload rapidly induces oxidative stress-mediated myocyte apoptosis and hypertrophy, Biochim Biophys Acta 2005, 1741:173-182
61. Mihl C, Dassen WR, Kuipers H: Cardiac remodelling: concentric versus eccentric hypertrophy in strength and endurance athletes, Neth Heart J 2008, 16:129-133
62. Khoynezhad A, Jalali Z, Tortolani AJ: Apoptosis: pathophysiology and therapeutic implications for the cardiac surgeon, Ann Thorac Surg 2004, 78:1109-1118
63. Lago RM, Singh PP, Nesto RW: Congestive heart failure and cardiovascular death in patients with prediabetes and type 2 diabetes given thiazolidinediones: a meta-analysis of randomised clinical trials, Lancet 2007, 370:1129-1136
64. Rosen CJ: The rosiglitazone story--lessons from an FDA Advisory Committee meeting, N Engl J Med 2007, 357:844-846
65. Hirsch IB, Kelly J, Cooper S: Pulmonary edema associated with troglitazone therapy, Archives of internal medicine 1999, 159:1811
66. Fuchtenbusch M, Standl E, Schatz H: Clinical efficacy of new thiazolidinediones and glinides in the treatment of type 2 diabetes mellitus, Exp Clin Endocrinol Diabetes 2000, 108:151-163
67. Thomas ML, Lloyd SJ: Pulmonary edema associated with rosiglitazone and troglitazone, The Annals of pharmacotherapy 2001, 35:123-124
68. Tsai YS, Kim HJ, Takahashi N, Kim HS, Hagaman JR, Kim JK, Maeda N: Hypertension and abnormal fat distribution but not insulin resistance in mice with P465L PPARgamma, J Clin Invest 2004, 114:240-249
69. Bligh EG, Dyer WJ: A rapid method of total lipid extraction and purification, Can J Biochem Physiol 1959, 37:911-917
70. Kis A, Murdoch C, Zhang M, Siva A, Rodriguez-Cuenca S, Carobbio S, Lukasik A, Blount M, O'Rahilly S, Gray SL, Shah AM, Vidal-Puig A: Defective peroxisomal proliferators activated receptor gamma activity due to dominant-negative mutation synergizes with hypertension to accelerate cardiac fibrosis in mice, Eur J Heart Fail 2009, 11:533-541
71. Bos JM, Ackerman MJ: Z-disc genes in hypertrophic cardiomyopathy: stretching the cardiomyopathies?, J Am Coll Cardiol 2010, 55:1136-1138
72. Sugden PH, Clerk A: "Stress-responsive" mitogen-activated protein kinases (c-Jun N-terminal kinases and p38 mitogen-activated protein kinases) in the myocardium, Circ Res 1998, 83:345-352
73. Juurlink DN, Gomes T, Lipscombe LL, Austin PC, Hux JE, Mamdani MM: Adverse cardiovascular events during treatment with pioglitazone and rosiglitazone: population based cohort study, BMJ 2009, 339:b2942
74. Caglayan E, Stauber B, Collins AR, Lyon CJ, Yin F, Liu J, Rosenkranz S, Erdmann E, Peterson LE, Ross RS, Tangirala RK, Hsueh WA: Differential roles of cardiomyocyte and macrophage peroxisome proliferator-activated receptor gamma in cardiac fibrosis, Diabetes 2008, 57:2470-2479
75. Brunmair B, Gras F, Neschen S, Roden M, Wagner L, Waldhausl W, Furnsinn C: Direct thiazolidinedione action on isolated rat skeletal muscle fuel handling is independent of peroxisome proliferator-activated receptor-gamma-mediated changes in gene expression, Diabetes 2001, 50:2309-2315
76. Sena S, Rasmussen IR, Wende AR, McQueen AP, Theobald HA, Wilde N, Pereira RO, Litwin SE, Berger JP, Abel ED: Cardiac hypertrophy caused by peroxisome proliferator- activated receptor-gamma agonist treatment occurs independently of changes in myocardial insulin signaling, Endocrinology 2007, 148:6047-6053
77. Edgley AJ, Thalen PG, Dahllof B, Lanne B, Ljung B, Oakes ND: PPARgamma agonist induced cardiac enlargement is associated with reduced fatty acid and increased glucose utilization in myocardium of Wistar rats, Eur J Pharmacol 2006, 538:195-206
78. Bueno OF, Molkentin JD: Involvement of extracellular signal-regulated kinases 1/2 in cardiac hypertrophy and cell death, Circ Res 2002, 91:776-781
79. Borsting E, Cheng VP, Glass CK, Vallon V, Cunard R: Peroxisome proliferator-activated receptor-gamma agonists repress epithelial sodium channel expression in the kidney, Am J Physiol Renal Physiol 2012, 302:F540-551
80. Nofziger C, Blazer-Yost BL: PPARgamma agonists, modulation of ion transporters, and fluid retention, J Am Soc Nephrol 2009, 20:2481-2483
81. Vallon V, Hummler E, Rieg T, Pochynyuk O, Bugaj V, Schroth J, Dechenes G, Rossier B, Cunard R, Stockand J: Thiazolidinedione-induced fluid retention is independent of collecting duct alphaENaC activity, J Am Soc Nephrol 2009, 20:721-729
82. Goltsman I, Wang X, Lavallie ER, Diblasio-Smith EA, Ovcharenko E, Hoffman A, Abassi Z, Feuerstein GZ, Winaver J: Effects of chronic rosiglitazone treatment on renal handling of salt and water in rats with volume-overload congestive heart failure, Circ Heart Fail 2011, 4:345-354
83. Chen L, Yang B, McNulty JA, Clifton LG, Binz JG, Grimes AM, Strum JC, Harrington WW, Chen Z, Balon TW, Stimpson SA, Brown KK: GI262570, a peroxisome proliferator-activated receptor {gamma} agonist, changes electrolytes and water reabsorption from the distal nephron in rats, J Pharmacol Exp Ther 2005, 312:718-725
84. Karalliedde J, Buckingham R, Starkie M, Lorand D, Stewart M, Viberti G: Effect of various diuretic treatments on rosiglitazone-induced fluid retention, J Am Soc Nephrol 2006, 17:3482-3490
85. Rennings AJ, Russel FG, Li Y, Deen PM, Masereeuw R, Tack CJ, Smits P: Preserved response to diuretics in rosiglitazone-treated subjects with insulin resistance: a randomized double-blind placebo-controlled crossover study, Clin Pharmacol Ther 2011, 89:587-594
86. Booth RE, Johnson JP, Stockand JD: Aldosterone, Adv Physiol Educ 2002, 26:8-20
87. Giles TD, Sander GE: Effects of thiazolidinediones on blood pressure, Curr Hypertens Rep 2007, 9:332-337
88. Festuccia WT, Laplante M, Brule S, Houde VP, Achouba A, Lachance D, Pedrosa ML, Silva ME, Guerra-Sa R, Couet J, Arsenault M, Marette A, Deshaies Y: Rosiglitazone-induced heart remodelling is associated with enhanced turnover of myofibrillar protein and mTOR activation, J Mol Cell Cardiol 2009, 47:85-95
89. Barbieri M, Di Filippo C, Esposito A, Marfella R, Rizzo MR, D'Amico M, Ferraraccio F, Di Ronza C, Duan SZ, Mortensen RM, Rossi F, Paolisso G: Effects of PPARs agonists on cardiac metabolism in littermate and cardiomyocyte-specific PPAR-gamma-knockout (CM-PGKO) mice, PLoS One 2012, 7:e35999
90. Gilde AJ, van der Lee KA, Willemsen PH, Chinetti G, van der Leij FR, van der Vusse GJ, Staels B, van Bilsen M: Peroxisome proliferator-activated receptor (PPAR) alpha and PPARbeta/delta, but not PPARgamma, modulate the expression of genes involved in cardiac lipid metabolism, Circ Res 2003, 92:518-524
91. Lincoff AM, Wolski K, Nicholls SJ, Nissen SE: Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus: a meta-analysis of randomized trials, JAMA 2007, 298:1180-1188
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