臺灣博碩士論文加值系統

研究背景
安體舒通(醛類脂醇拮抗劑)可以改善糖尿病與心衰竭引發的血管內皮細胞功能不佳˳雖然如此,但是,它在非糖尿病引起慢性腎衰竭中是否能改善血管系統則不確定˳我們使用5/6腎切除老鼠建構依個腎衰竭模型,探討是否醛類脂醇拮抗劑可以影響並減少血管內皮細胞功能不佳,並研究其中機制˳
研究方法
24隻史-道二氏大鼠分為四組:我們給第一組大鼠施予假手術;我們給第二組大鼠施予5/6腎切除手術;第三組大鼠施予5/6腎切除手術並給予糖化最終產物裂解劑;第四組大鼠接受5/6腎切除手術並投予安體舒通˳我們比較這四組大鼠乙醯膽鹼作用血管內皮擴張不佳是否有統計上差異?我們將四組大鼠的部份主動脈作組織切片染色,比較糖化最終產物及其受器,內皮細胞一氧化氮合成酶,及磷酸化內皮細胞一氧化氮合成酶的組織沉積量是否有不同,為了研究其可能機轉,我們利用人的主動脈內皮細胞進行細胞培養實驗˳我們首先將人主動脈內皮細胞施加糖化最終產物(0, 100, 200, 500μg/mL)評估內皮細胞一氧化氮合成酶,及磷酸化內皮細胞一氧化氮合成酶是否被抑制,我們再加入安體舒通(醛類脂醇拮抗劑)(0, 0.1, 1, 10μM)並評估兩組之間的內皮細胞一氧化氮合成酶,及磷酸化內皮細胞一氧化氮合成酶蛋白是否增加,再來我們將人的主動脈內皮細胞加入2’, 7’,-二氯二氫螢光素二乙酸脂(2.5μM),或紅色粒線體過氧化物螢光探針比較糖化最終產物與安體舒通是否影響細胞內與粒線體內過氧化物產生?兩組之間的實驗數據比較我們使用學生t檢定,三組以上的實驗數據用變異數分析,事後比較則用費雪LSD檢定˳
研究結果
相較於第一組,編號第二組大鼠的乙醯膽鹼相關血管內皮擴張功能不佳˳相較於第二組,編號第三組與編號第四組大鼠的乙醯膽鹼相關血管內皮擴張功能則顯著改善˳我們使用人的主動脈血管內皮細胞做細胞實驗來進一步探討其機轉,我們注意到當人的主動脈內皮細胞接受糖化最終產物(200μg/mL)刺激後,NAD-依賴性去乙醯化酶(SIRT-3)的產生減少,內皮細胞一氧化氮合成酶磷酸化減少,以及過氧化物堆積˳當我們對人的主動脈內皮細胞加入安體舒通(10μM)後,上述反應會減少˳我們更注意到當我們對人主動脈內皮細胞內加入NAD-依賴性去乙醯化酶(SIRT-3)抑制劑(tenolvin-6)(1μM)後,安體舒通(10μM)減少過氧化物堆積並增加血管內皮細胞一氧化氮合成酶磷酸化的影響就被抑制了˳
結論
安體舒通可以藉由抑制糖化最終產物與其受體作用路徑活化,增加NAD-依賴性去乙醯化酶(SIRT-3)產生,進而減少NADPH氧化酶活化,減少過氧化物的堆積來改善腎衰竭模式中血管內皮細胞功能不佳˳

Background
Spironolactone (A mineralocorticoid receptor antagonist; Aldactone) could reduce endothelial dysfunction (ED) in congestive heart failure and diabetes. Its beneficial effect in the cardiovascular system is unclear in non-diabetic renal failure model. We designed a study to discuss if spironolactone could reduce ED in a 5/6 nephrectomy non-diabetic renal failure model, and to explore the possible mechanism.
Methods
24 Sprague-Dawley rats were divided into 4 groups. A non-diabetic renal failure model was created with the 5/6 radical nephrectomy approach. The 4 groups includes: Sham-procedure group (Group1), chronic kidney disease created by 5/6 nephrectomy approach (CKD; Group2), CKD + ALT-711 (advanced glycation end products [AGEs] breaker; Group 3), and CKD + aldactone (Group4) groups. Acetylcholine (Ach)-associated vasodilating responses were compared between the groups. Immunohistochemical stains for specimens from segments of Sprague-Dawley rats’ thoracic aorta were performed to compare the different amounts of AGEs, receptor for AGEs (RAGE), endothelial nitric oxide synthase (eNOS), and phosphorylation of eNOS (p-eNOS) between groups. To discuss the underlying mechanism, we used human aortic endothelial cells (HAECs) for in-vitro assays. First, we treated HAECs with different concenstrations of AGEs (0, 100, 200, 500μg/mL) to evaluate whether phosphorylation of eNOS could be attenuated, and pretreatment with spironolactone (0, 0.1, 1, 10μM) could reactivate the eNOS in a concentration-dependent manner. Second, we further tested whether the treatment of HAECs with AGEs could induce the production of intracellular and mitochondrial oxidative stress, and pretreatment with spironolactone could abrogate the production of intracellular and mitochondrial oxidative stress, We treated the HAECs with 2.5μM 2’,7’-Dichlorodihydrofluorescein diacetate (DCFH-DA) or 5μM MitoSox red and measure with the TECAN Infinite M1000 plate reader. To further investigate the role of sirtuin-3 (SIRT3) in the spironolactone’s influence on the inhibition of AGEs/RAGE pathway, we further investigated whether production of SIRT3 would be attenuated in HAECs stimulated with AGEs (200μM). Then, we added spironolactone with uptitrating manner (0, 0.1, 1, 10μM) in AGEs-treated HAECs to investigate if the reduction of SIRT3 production and dephosphrylation of eNOS could be reverse. Finally, we conducted confocal experiment to test whether production of NADPH oxidase type II (NOX-2) could be influenced by treatments with AGEs, spironolactone or tenolvin-6. This implied the source of increased cytosolic oxidative stress. Significance of the differences between 2 groups were conducted with the paired student’s t test. Comparisons of differences between 3 or more groups were conducted by one-way analysis of variance (ANOVA) with post-hoc analysis with LSD method.
Results
In comparison with Group 1, Group 2 has a significantly impaired Ach-associated vasodilating response. Group 3 and 4 has improved vasodilating responses. Immunohistochemical stain demonstrated that increased tissue accumulation of AGEs, RAGE could be expected in Group 2 than in other groups. The phosphorylation of eNOS was lower in the Group 2 than in the other 3 grousp. The tissue accumulation of eNOS is comparable between the Group 2 and the other 3 groups. To investigate the possible mechanism, we conducted an in-vitro study by using cultured HAECs. We found significant downregulation of sirtuin-3 (SIRT3) protein, reduced p-eNOS at serine 1177, and upregulation of intracellular oxidative stress in HAECs treated with AGEs (200μg/mL). The effects were counter-regulated when we pretreated HAECs with spironolactone (10μM). In addition, the increased p-eNOS activation by spironolactone was off-set when the we pretreated HAECs with tenolvin-6 (1μM), a SIRT3 inhibitor. Confocal microscopy displayed increased NOX-2 production when HAECs were stimulated with AGEs (200μg/mL), and the production of NOX-2 was counterregulated when we pretreated the AGEs-stimulated HAECs with aldactone (10μM). Furthermore, the effect of aldactone was reduced when we pretreated the HAECs with SIRT-3 inhibitor (enolvin-6)(1μM).
Conclusions
Spironolactone may reduce ED in 5/6 radical nephrectomy renal failure rats via inhibiting the AGEs/RAGE axis, upregulation of SIRT3, and nicotinamide adenine dinucleotide phosphate oxidase-2 (NOX-2) and its related oxidative stress attenuation.

目次
1. 封面
2. 學位考試審定書影本 PI
3. 中國醫藥大學研究生無違反學術倫理聲明書 PII
4. 誌謝 PIII
5. 中文摘要 PIV
6. 英文摘要 PVII
7. 論文正文 P1
第一章節 P5
第一章 前言 P6
第一節 研究背景 P6
第二節 研究目的 P6
第二章 研究方法 P7
第一節 研究設計 P7
第二節 研究材料與方法 P8
第三節 統計方法 P9
第三章 研究結果 P11
第一節 描述性統計分析 P11
第二節 推論性統計分析 P11
第四章 討論 P13
第一節 結果討論 P13
第二節 其它相關性討論 P13
第三節 研究限制 P15
第五章 結論與建議 P16
第一節 結論 P16
第二節 建議 P16
第二章節 P24
第一章 前言 P25
第一節 研究背景 P25
第二節 研究目的 P26
第二章 研究方法 P27
第一節 研究設計 P27
第二節 研究材料與方法 P29
第三節 統計方法 P31
第三章 研究結果 P32
第一節 描述性統計分析 P32
第二節 推論性統計分析 P34
第四章 討論 P36
第一節 結果討論 P36
第二節 其它相關性討論 P38
第三節 研究限制 P39
第五章 結論與建議 P41
第一節 結論 P41
第二節 建議 P41
第三章節 P48
第一章 前言 P49
第一節 研究背景 P49
第二節 研究目的 P50
第二章 研究方法 P51
第一節 研究設計 P51
第二節 研究材料與方法 P52
第三節 統計方法 P55
第三章 研究結果 P56
第一節 描述性統計分析 P56
第二節 推論性統計分析 P57
第四章 討論 P59
第一節 結果討論 P59
第二節 其它相關性討論 P60
第三節 研究限制 P62
第五章 結論與建議 P64
第一節 結論 P64
第二節 建議 P64
第四章節 P75
第一章 前言 P76
第一節 研究背景 P76
第二節 研究目的 P77
第二章 研究方法 P78
第一節 研究設計 P78
第二節 研究材料與方法 P79
第三節 統計方法 P86
第三章 研究結果 P87
第一節 描述性統計分析 P87
第二節 推論性統計分析 P89
第四章 討論 P93
第一節 結果討論 P93
第二節 其它相關性討論 P94
第三節 研究限制 P96
第五章 結論與建議 P98
第一節 結論 P98
第二節 建議 P98
8. 參考書目 P112
圖表目次
第一章節
1. Table 1 P17
2. Table 2 P18
3. Table 3 P19
4. Table 4 P20
5. Table 5 P21
6. Figure 1 P22
7. Figure 2 P23
第二章節
1. Table 1 P42
2. Table 2 P43
3. Table 3 P44
4. Table 4 P45
5. Figure 1 P46
6. Figure 2 P47
第三章節
1. Table 1 P65
2. Table 2 P66
3. Table 3 P67
4. Table 4 P68
5. Table 5 P70
6. Figure 1 P71
7. Figure 2 P72
8. Figure 3 P73
9. Figure 4 P74
第四章節
1. Table 1 P100
2. Figure 1 P101
3. Figure 2 P102
4. Figure 3 P103
5. Figure 4 P104
6. Figure 5 P105
7. Figure 6 P106
8. Figure 7 P107
9. Figure 8 P108
10. Figure 9 P109
11. Figure 10 P110
12. Figure 11 P111

1.Shafi T, Meyer TW, Hostetter TH, Melamed ML, Parekh RS, Hwang S, et al. Free levels of selected organic solutes and cardiovascular morbidity and mortality in hemodialysis patients: Results from retained organic solutes and clinical outcomes (ROSCO) investigators. PLoS One 2015; 10(5): e0126048
2.U.S. Renal Data system, USRDS 2013 Annual Data Report: Atlas of chronic kidney disease and end stage renal disease in the United States, National Institute of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland. 2015; 4: 2.
3.Parfrey PS, Foley RN. The clinical epidemiology of cardiac disease in chronic renal failure. J Am Soc Nephrol 1999; 10: 1606-1615.
4.Foley RN, Murray AM, Li S, Herzog CA, McBean AM, Eggers PW, et al. Chronic kidney disease and the risk for cardiovascular disease, renal replacement, and death in the united states medicare population, 1998-1999. J Am Soc Nephrol 2005; 16: 489-495.
5.Himmelfarb J, Stenvinkel P, Ikizler TA, Hakim RM. The elephant in uremia: oxidant stress as a unifying concept of cardiovascular disease in uremia. Kidney Int 2002; 62: 1524-1538.
6.Widlansky ME, Gokce N, Keaney JF, Vita JA. The clinical implications of endothelial dysfunction. J Am Coll Cardiol 2003; 42: 1149-1160.
7.Miyazawa T, Nakagawa K, Shimasaki S, Nagai R. Lipid glycation and protein glycation in diabetes and atherosclerosis. Amino Acids 2012; 42(4): 1163-1170.
8.Weiss MF, Erhard P, Kader-Attia FA, Wu YC, Deoreo PB, Araki A, et al. Mechanisms for the formation of glycoxidation products in end-stage renal disease. Kidney Int 2000; 57: 2571-2585.
9.Miyata T, Saito A, Kurokawa K, de Strihou CVY. Advanced glycation and lipoxidation end products: reactive carbonyl compounds-related uraemic toxicity. Nephrol Dial Transplant 2001; 16(suppl 4): 8-11.
10.Sakata N, Noma A, Yamamoto Y, Okamoto K, Meng J, Takebayashi S, et al. Modification of elastin by pentosidine is associated with the calcification of aortic media in patients with end-stage renal disease. Nephrol Dial Transplant 2003; 18: 1601-1609.
11.Brunet P, Gondouin B, Duval-Sabatier A, Dou L, Cerini C, Dignat-George F, et al. Does uremia cause vascular dysfunction? Kidney Blood Press Res 2011; 34: 284-290.
12.Soro-Paavonen A, Zhang WZ, Venardos K, Coughlan MT, Harris E, Tong DC, et al. Advanced glycation end-products induce vascular dysfunction via resistance to nitric oxide and suppression of endothelial nitric oxide synthase. J Hypertens 2010; 28: 780-788.
13.Raj DSC, Choudhury D, Welbourne TC, Levi M. Advanced glycation end products: A nephrologist’s perspective. Am J Kidney Dis 2000; 35(3): 365-80.
14.Wagner Z, Molnár M, Molnár GA, Tamaskó M, Laczy B, Wagner L et al. Serum carboxymethyllysine predicts mortality in hemodialysis patients. Am J Kidney Dis 2006; 47(2): 294-300.
15.Schwedler SB, Metzger T, Schinzel R, Wanner C. Advanced glycation end products and mortality in hemodialysis patients. Kidney Int 2002; 62: 301-310.
16.National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis 2002;39:S1-S226.
17.Shechter M, Issachar A, Marai I, Koren-Morag N, Freinark D, Shahar Y, et al. Long-term association of brachial artery flow-mediated vasodilatation and cardiovascular events in middle-aged subjects with no apparent heart disease. Int J Cardiol 2009; 134: 52-58.
18.Raitakari OT, Celermajer DS. Flow-mediated dilatation. Br J Clin Pharmacol 2000; 50: 397-404.
19.Iwamoto Y, Maruhashi T, Fujii Y, Idei N, Fujimura N, Mikami S, et al. Intimal-media thickness of brachial artery, vascular function, and cardiovascular risk factors. Arterioscler Thromb Vasc Biol 2012; 32: 2295-2303.
20.Meerwaldt R, Graaff R, Oomen PHN, Links TP, Jager JJ, Alderson NL, et al. Simple non-invasive assessment of advanced glycation end product accumulation. Diabetologia 2004; 47: 1324-330.
21.de Vos LC, Noordzij MJ, Mulder DJ, Smit AJ, Lutgers HL, Dullaart RP, et al. Skin autofluorescence as a measure of advanced glycation end product deposition is elevated in peripheral artery disease. Arterioscler Thromb Vasc Biol 2013; 33(1): 131-138.
22.Teragawa H, Kato M, Kurokawa J, Yamagata T, Matsuura H, Chayama K. Usefulness of flow-mediated dilation of the brachial artery and/or the intimal-media thickness of the carotid artery in predicting coronary narrowing in patients suspected of having coronary artery disease. Am J Cardiol 2001; 15: 88(10): 1147-1151.
23.Monnier VM, Bautista O, Kenny D, Sell DR, Fogarty J, Dahms W, et al. skin collagen ancillary study group. Skin collagen glycation, glycoxidation, and crosslinking are lower in subjects with long-term intensive versus conventional therapy of type 1 diabetes. Diabetes 1999; 48(4): 870-880.
24.Monnier VM, Sell DR, Genuth S. Glycation products as markers and predictors of the progression of diabetic complications. Ann N Y Acad Sci 2005; 1043: 567-581.
25.Tanaka K, Tani Y, Asai J, Nemoto F, Kusano Y, Suzuki H, et al. Skin autofluorescence is associated with severity of vascular complications in Japanese patients with type 2 diabetes. Diabet Med 2012; 29: 492-500.
26.Mulder DJ, van Haelst PL, Graaff R, Gans RO, Zijlstra F, Smit AJ. Skin autofluorescence is elevated in acute myocardial infarction and is associated with the one-year incidence of major adverse cardiac events. Neth Heart J 2009; 17(4): 162-168.
27.Mulder DJ, van Haelst PL, Gross S, de Leeuw K, Bijzet J, Graaff R, et al. Skin autofluorescence is elevated in patients with stable coronary artery disease and is associated with serum levels of neopterin and the soluble receptor for advanced glycation end products. Atherosclerosis 2008; 197(1): 217-223.
28.Noordzij MJ, Lefrandt JD, Loeffen EA, Saleem BR, Meerwaldt R, Lutgers HL et al. Skin autofluorescence is increased in patients with carotid artery stenosis and peripheral artery disease. Int J Cardiovasc Imaging 2012; 28(2): 431-438.
29.Ueno H, Koyama H, Tanaka S, Fukumoto S, Shinohara K, Shoji T, et al. Skin autofluorescence, marker for advanced glycation end product accumulation, is associated with arterial stiffness in patients with end-stage renal disease. Metabolism 2008; 57(10): 1452-1457.
30.Kocak H, Gumuslu S, Sahin E, Ceken K, Gocmen YA, Yakupoglu G, et al. Advanced oxidative protein products are independently associated with endothelial function in peritoneal dialysis patients. Nephrology 2009; 14: 273-280.
31.Sönmez Uydeş-Doğan B, Topal G, Takir S, Ilkay Alp F, Kaleli D, Ozdemir O. Relaxant effects of pravastatin, atorvastatin, and cerivastatin on isolated rat aortic rings. Life Sci 2005; 76(15): 1771-1786.
32.Deng HF, Xiong Y. Effect of pravastatin on impaired endothelium-dependent relaxation induced by lysophosphatidylcholine in rat aorta. Acta Pharmacol Sin 2005; 26(1): 92-98.
33.Nazratun N, Mahmood AA, Kuppusamy UR, Ahmad TS, Tan SY. Diabetes mellitus exacerbates advanced glycation end product accumulation in the veins of end-stage renal failure patients. Vasc Med 2006; 11: 245-250.
34.Zhou Y, Yu Z, Jia H, Sun F, Ma L, Guo R, et al. Association of serum pentosidine with arterial stiffness in hemodialysis patients. Artif Organs 2010; 34(3): 193-199.
35.Contreras I, Reiser KM, Martinez N, Giansante E, Lopez T, Suarez N, et al. Effects of aspirin or basic amino acids on collagen cross-links and complications in NIDDM. Diabetes Care 1997; 20(5): 832-835.
36.Jadoul M, Ueda Y, Yasuda Y, Saito A, Robert A, Ishida N, et al. Influence of hemodialysis membrane type on pentosidine plasma level, a marker of carbonyl stress. Kidney Int 1999; 55: 2487-2492.
37.Suliman ME, Heimbürger O, Bárány P, Anderstam B, Pecoits-Filho R, Rodríguez Ayala E, et al. Plasma pentosidine is associated with inflammation and malnutrition in end-stage renal disease patients starting on dialysis therapy. J Am Soc Nephrol 2003; 14(6): 1614-1622.
38.de Simone G, Verdecchia P, Pede S, Gorini M, Maggioni AP, on behalf of the
MAVI Investigators. Prognosis of inappropriate left ventricular mass in hypertension. The MAVI study. Hypertension. 2002;40:470-6.
39.Huang BT, Peng Y, Liu W, Zhang C, Juang FY, Wang PJ, et al. Inappropriate left ventricular mass and poor outcomes in patients with angina pectoris and normal ejection fraction. Coron Artery Dis. 2015;26:163-9.
40.Cioffi G, Rossi A, Zoppini G, Targher G, de Simone G, Devereux RB, et al. Inappropriate left ventricular mass independently predicts cardiovascular mortality in patients with type 2 diabetes. Int J Cardiol. 2013;168(5):4953-6.
41.Muiesan ML, Salvetti M, Paini A, Monteduro C, Galbassini G, Bonzi B, et al. Inappropriate left ventricular mass changes during treatment adversely affects cardiovascular prognosis in hypertensive patients. Hypertension. 2007;49:1077-83.
42.Zieman SJ, Kass DA. Advanced glycation end product cross-linking:
Pathophysiologic role and therapeutic target in cardiovascular disease. CHF. 2004;10:144-51.
43.Hartlog JWL, Voors AA, Bakker SJL, Smit AJ, van Veldhuisen DJ. Advanced
glycation end-products (AGEs) and heart failure: Pathophysiology and clinical implications. Eur J Heart Fail. 2007;9:1146-55.
44.Schäfer S, Huber J, Wihler C, Rütten H, Busch AE, Linz W. Impaired left
ventricular relaxation in type 2 diabetic rats is related to myocardial accumulation of Nε-(carboxymethyl)lysine. Eur J Heart Fail. 2006;8:2-6.
45.van Heerebeck L, Hamdani N, Handoko L, Falcao-Pires I, Musters RJ,
Kupreishvili K, et al. Diastolic stiffness of the failing diabetic heart: Importance of fibrosis, advanced glycation end products, and myocyte resting tension. Circulation. 2008;117:43-51.
46.Striker LJ, Striker GE. Administration of AGEs in vivo induces extracellular matrix gene expression. Nephrol Dial Transplant. 1996;11[suppl 5]:62-5.
47.Vélayoudom-Céphise FL, Rajaobelina K, Helmer C, Nov S, Pupier E, Blanco L, et al. Skin autofluorescence predicts cardio-renal outcome in type 1 diabetes: a longitudinal study. Cardiovasc Diabetol. 2016;15:127-34.
48.Jiang JP, Chen PY, Chen JH, Yu XQ, Xie D, Mei CL, et al. Accumulation of tissue advanced glycation end products correlated with glucose exposure dose and associated with cardiovascular morbidity in patients on peritoneal dialysis. Atherosclerosis. 2012;224:187-94.
49.Wang CC, Wang YC, Wang GJ, Shen MY, Chang YL, Liou SY, et al. Skin autofluorescence is associated with endothelial dysfunction in uremic subjects on hemodialysis. PLoS One. 2016;11(1):e0147771.
50.Lang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E, Pellikka PA,
et al. Recommendations for chamber quantification: A report from the American Society of Echocardiography’s guidelines and the chamber quantification writing group, developed in conjunction with the European association of echocardiography, a branch of the European Society of Cardiology. J Am Soc Echocardiogr. 2005;18:1440-63.
51.Nagueh SF, Appleton CP, Gillebert TC, Marino PN, Oh JK, Smiseth OA, et al. Recommendations for the evaluation of left ventricular diastolic function by echocardiography. J Am Soc Echocardiogr. 2009;22(2):107-33.
52.Devereux RB, Alonso DR, Lutas EM, Gottlieb GJ, Campo E, Sachs I, et al.
Echocardiographic assessment of left ventricular hypertrophy: comparison to necropsy findings. Am J Cardiol. 1986;57(6):450-8.
53.Su HM, Lin TH, Hsu PC, Lee CS, Lee WH, Chen SC, et al. Association of chronic kidney disease and peripheral artery disease with inappropriate left ventricular mass. PLoS One. 2012;7:10:e48422.
54.Cioffi G, Tarantini L, Frizzi R, Stefenelli C, Furlanello F, de Simone G. Chronic
Kidney disease elicits excessive increase in left ventricular mass growth in patients at increased risk for cardiovascular events. J Hypertens. 2011;29:565-73.
55.Maunganidze F, Norton GR, Maseko MJ, Libhaber CD, Majane OHI, Sareli P,
et al. Relationship between glomerular dysfunction and left ventricular mass independent of haemodynamic factors in a community sample. J Hypertens. 2013;31:568-75.
56.Ratto E, Leocini G, Viazzi F, Bezante GP, Falqui V, Parodi A, et al. Inappropriate left ventricular mass is associated with microalbuminuria independently of left ventricular hypertrophy in primary hypertension. J Hypertens. 2008;26:345-50.
57.Himmelfarb J, Stenvinkel P, Ikizler TA, Hakim RM. The elephant in uremia:
Oxidant stress as a unifying concept of cardiovascular disease in uremia. Kidney Int. 2002;62:1524-38.
58.Little WC, Zile MR, Kitzman DW, Hundley WG, O’Brien TX, Degroof RC. The
Effect of alagebrium chloride (ALT-711), a novel glucose cross-link breaker, in the treatment of elderly patients with diastolic heart failure. J Card Fail. 2005;11:191-5.
59.de Simone G, Pasanisi F, Contaldo F. Link of nonhemodynamic factors to
hemodynamic determinants of left ventricular hypertrophy. Hypertension. 2001;38:13-8.
60.Celentano A, Pietropaolo I, Palmieri V, Esposito NDP, Crivaro M, Cirillo F,
et al. Inappropriate left ventricular mass and angiotensin converting enzyme gene polymorphism. J Hum Hypertensions. 2001;15:811-3.
61.Gregori M, Tocci G, Marra A, Pignatelli G, Santolamazza C, Befani A,
et al. Inadequate RAAS suppression is associated with excessive left ventricular mass and systo-diastolic dysfunction. Clin Res Cardiol. 2013;102:725-33.
62.López B, Castellano JM, González A, Barba J, Díez J. Association of increased
plasma cardiotrophin-1 with inappropriate left ventricular mass in essential hypertension. Hypertension. 2007;50:977-83.
63.Petrova R, Yamamoto Y, Muraki K, Yonekura H, Sakurai S, Watanabe T, et al. Advanced glycation endproduct-induced calcium handling impairment in mouse cardiac myocytes. J Mol Cell Cardiol. 2002;34:1425-31.
64.Hartog JWL, Willemsen S, van Veldhuisen DJ, Posma JL, van Wijk LM, Hummel
YM, for the BENEFICIAL investigators. Effect of alagebrium, an advanced glycation endproduct breaker, on exercise tolerance and cardiac function in patients with chronic heart failure. Eur J Heart Fail. 2011;13:899-908.
65.Libhaber CD, Norton GR, Maseko MJ, Majane OHI, Millen AME, Maunganidze F, et al. Relationship between inappropriate left ventricular hypertrophy and ejection fraction independent of absolute or indexed mass in a community sample of black African ancestry. J Hypertens. 2013;31:169-76.
66.de Simone G, Kitzman DW, Palmieri V, Liu JE, Oberman A, Hopkins PN, et al. Association of inappropriate left ventricular mass with systolic and diastolic dysfunction. The HyperGEN Study. Am J Hypertens. 2004;17:828-33.
67.Mureddu GF, Cioffi G, Stefenelli C, Boccanelli. Relationships of the
appropriateness of left ventricular mass to left atrial size and function in arterial hypertension. J Cardiovasc Med. 2007;8:445-52.
68.Mureddu GF, Pasanisi F, Palmieri V, Celentano A, Contaldo F, de Simone G.
Appropriate or inappropriate left ventricular mass in the presence or absence of prognostically adverse left ventricular hypertrophy. J Hypertens. 2001;19:1113-9.
69.Hofmann B, Jacobs K, Navarrete Santos A, Wienke A, Silber RE, Simm A.
Relationship between cardiac tissue glycation and skin autofluorescence in patients with coronary artery disease. Diabete Metab. 2015;41:410-5.
70.Soro-Paavonen A, Zhang WZ, Venardos K, Coughlan MT, Harris E, Tong DCK, et al. Advanced glycation end-products induce vascular dysfunction via resistance to nitric oxide and suppression of endothelial nitric oxide synthase. J Hypertens. 2010;28:780-8.
71.Aronson D. Cross-linking of glycated collagen in the pathogenesis of arterial and myocardial stiffening of aging and diabetes. J Hypertens. 2003;21:3-12.
72.Koetsier M, Lutgers HL, de Jonge C, Links TP, Smit AJ, Graaff R. Reference values of skin autofluorescence. Diabetes Technol Ther. 2010;12(5):399-403.
73.Kellow NJ, Coughlan MT, Reid CM. Association between habitual dietary and lifestyle behaviours and skin autofluorescence (SAF), a marker of tissue accumulation of advanced glycation end-products (AGEs), in healthy adults. Eur J Nutr. 2017; Jun 27.
74.van Watteringe RP, Mook-Kanamori MJ, Slagter SN, van der Klauw MM, van Villet-Ostaptchouk JV, Graaff R, et al. The association between various smoking behaviors, cotinine biomarkers and skin autofluorescence, a marker for advanced glycation end product accumulation. PLoS ONE. 2017;12(6):e0179330.
75.Syngle A, Vohra K, Garg N, Kaur L, Chand P. Advanced glycation end-products inhibition improves endothelial dysfunction in rheumatoid arthritis. Int J Rheum Dis. 2012;15(1):45-55.
76.Arsov S, Graaff R, van Oeveren W, Stegmayr B, Sikole A, Rakhorst G, et al. Advanced glycation end-products and skin autofluorescence in end-stage renal disease: a review. Clin Chem Lab Med. 2014;52(1):11-20.
77.Lutger HL, Graaff R, Links TP, Ubink-Veltmaat LJ, Bilo HJ, Gans RO, et al. Skin autofluorescence as a noninvasive marker of vascular damage in patients with type 2 diabetes. Diabetes Care. 2006;29(12):2654-9.
78.Fraser SD, Roderick PJ, Mclntyre NJ, Harris S, Mclntyre CW, Fluck RJ, et al. Skin autofluorescence and all-cause mortality om stage 3 CKD. Clin J Am Soc Nephrol. 2014;9:1361-8.
79.de Vos LC, Mulder DJ, Smit AJ, Dullaart RPF, Kleefstra N, Lijfering WM, et al. Skin autofluorescence is associated with 5-year mortality and cardiovascular events in patients with peripheral artery disease. Arterioscler Throm Vasc Biol. 2014;34:933-8.
80.Winston G, Palmas W, Lima J, Polak J, Bertoni A, Burke G, et al. Pulse pressure and subclinical cardiovascular disease in the Multi-Ethnic Study of Atherosclerosis. Am J Hypertens. 2013;26(5):636-42.
81.International Expert Committee report on the role of the A1C assay in the diagnosis of diabetes. Diabetes Care. 2009;32:1327-1334.
82.Da Moura Semedo C, Webb M, Waller H, Khunti K, Davies M. Skin autofluorescence, a non-invasive marker of advanced glycation end products: clinical relevance and limitations. Postgrad Med J. 2017;93:289-94.
83.Coutinho T, Borlaug B, Pellikka P, Turner S, Kullo I. Sex differences in arterial stiffness and ventricular-arterial interactions. J Am Coll Cardiol. 2013;61:96-103.
84.Nishimura RA, Otto CM, Bonow RO, Carabello BA, Erwin JP, Guyton RA, et al. 2014 AHA/ACC guideline for the management of patients with vulvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines. J Thorac Cardiovasc Surg. 2014;148:e1-e132.
85.Palombo C, Kozakova M. Arterial stiffness, atherosclerosis, and cardiovascular risk: Pathophysiologic mechanisms and emerging clinical indications. Vasc Pharmacol. 2016;77:38-47.
86.Viazzi F, Leoncini G, Parodi D, Ravera M, Ratto E, Vettoretti S, et al. Pulse pressure and subclinical cardiovascular damage in primary hypertension. Nephrol Dial Transplant. 2002;17:1779-1785.
87.Cauwenberghs N, Knez J, Tikhonoff V, D’hooge J, Kloch-Badelek M, Thijs L, et al. Doppler indexes of left ventricular systolic and diastolic function in relation to the arterial stiffness in a general population. J Hypertens. 2016;34:762-771.
88.Chirinos J, Kips J, Jacobs Jr. D, Brumback L, Duprez D, Kronmal R, et al. Arterial wave reflections and incident cardiovascular events and heart failure: MESA (Multiethnic Study of Atherosclerosis). J Am Coll Cardiol. 2012;60:2170-2177.
89.Pandey A, Khan H, Newman A, Lakatta E, Forman D, Butler J, et al. Arterial stiffness and risk of overall heart failure, heart failure with preserved ejection fraction, and heart failure with reduced ejection fraction: The Heart ABC Study (Health, Aging, and Body Composition). Hypertens. 2017;69:267-274.
90.Mitchell G, Hwang S, Vasan R, Larson M, Pencina M, Hamburg N, et al. Arterial stiffness and cardiovascular events: The Framingham Heart Study. Circ. 2010;121:505-511.
91.Sutton-Tyrrell K, Najjar S, Boudreau R, Venkitachalam L, Kupelian V, Simonsick E, et al. Elevated aortic pulse wave velocity, a marker of arterial stiffness, predicts cardiovascular events in well-functioning older adults. Circ. 2005;111:3384-3390.
92.Satoh-Asahara N, Kotani K, Yamakage H, Yamada T, Araki R, Okajima T, et al. Cardio-ankle vascular index predicts for the incidence of cardiovascular events in obese patients: A multicenter prospective cohort study (Japan Obesity and Metabolic Syndrome Study: JOMS). Atherosclerosis. 2015;242:461-468.
93.Pritchett A, Mahoney D, Jacobsen S, Rodeheffer R, Karon B, Redfield M. Diastolic dysfunction and left atrial volume: A population-based study. J Am Coll Cardiol. 2005;45:87-92.
94.Christensen N, Dahl J, Carter-Storch R, Bakkestr??m R, Pecini R, Steffensen F, et al. Relation of left atrial size, cardiac morphology, and clinical outcome in asymptomatic aortic stenosis. Am J Cardiol 2017;120:1877-1883.
95.Mosquera V, Bouzas-Mosquera A, González-Barbeito M, Bautista-Hernandez V, Muñiz J. Alvarez-García N, et al. Indexed left atrial size predicts all-cause and cardiovascular mortality in patients undergoing aortic valve surgery. J Thorac Cardiovasc Surg. 2017;153:1275-1284.
96.Thomas L, Abhayaratna W. Left atrial reverse remodeling: Mechanism, Evaluation, and clinical significance. J Am Coll Cardiol Img. 2017;10:65-77.
97.Kadappu K, Boyd A, Eshoo S, Haluska B, Yeo A, Marwick T, et al. Changes in left atrial volume in diabetes mellitus: more than diastolic dysfunction? Eur Heart J Cardiovasc Imaging. 2012;13:1016-1023.
98.Cerami C, Founds H, Nicholl I, Mitsuhashi T, Giordano D, Vanpatten S, et al. Tobacco smoke is a source of toxic reactive glycation products. Proc Natl Acad Sci U S A. 1997;94(25):13915-13920.
99.Foley RN, Murray AM, Li S, Herzog CA, Marshall McBean A, et al. Chronic kidney disease and the risk of cardiovascular disease, renal replacement, and death in the United States medicare population, 1998-1999. J Am Soc Nephrol. 2005;16:489-495.
100.Taki K, Takayama F, Tsuruta Y, Niwa T. Oxidative stress, advanced glycation end products, and coronary artery calcification in hemodialysis patients. Kidney Int. 2006;70:218-224.
101.Hartog JWL, Voors AA, Bakker SJL, Smit AJ, van Veldhuisen DJ. Advanced glycation end-products (AGEs) and heart failure: Pathophysiology and clinical implications. Eur J Heart Fail. 2007;9:1146-1155.
102.Miyata T, Wada Y, Cai Z, Iida Y, Horie K, Yasuda Y, et al. Implication of am increased oxidative stress in the formation of advanced glycation end products in patients with end-stage renal failure. Kidney Int. 1997;51:1170-1181.
103.Huang QF, Sheng CS, Liu M, Li FH, Li Y, Wang JG. Arterial stiffness and wave reflections in relation to plasma advanced glycation end products in a Chinese population. Am J Hypertens. 2013;26(6):754-761.
104.Schram MT, Schalkwijk CG, Bootsma AH, Fuller JH, Chaturvedi N, Stehouwer CDA, et al. Advanced glycation end products are associated with pulse pressure in type 1 diabetes. The EURODIAB prospective complications study. Hypertension. 2005;46:232-237.
105.Forbes JM, Yee TL, Thallas V, Lassila M, Candido R, Jandeleit-Dahm KA, et al. Advanced glycation end product interventions reduce diabetes-accelerated atherosclerosis. Diabetes. 2004;53:1813-1823.
106.Thai HM, Do BQ, Tran TD, Gaballa MA, Goldman S. Aldosterone antagonism impoves endothelial-dependent vasorelaxation in heart failure via upregulation of endothelial nitric oxide synthase production. J Card Fail. 2006;12(3):240-245.
107.Quach K, Lvtvyn L, Baigent C, Bueti J, Garg AX, Hawley C, et al. The safety and efficacy of mineralocorticoid receptor antagonists in patients who require dialysis: A systemic review and meta-analysis. Am J Kidney Dis. 2016.
108.Lin C, Zhang Q, Zhang H, Lin A. Long-term effects of low-dose spironolactone on chronic dialysis patients: A randomized placebo-controlled study. J Clin Hypertens. 2016;18(2):121-128.
109.Toba H, Nakashima K, Oshima Y, Kojima Y, Tojo C, Nakano A, Wang J, Kobara M, Nakata T. Erytheropoietin prevents vascular inflammation and oxidative stress in subtotal nephrectomized rat aorta beyond harmatopoiesis. Clin Exp Pharmacol. Physiol. 2010;37:1139-1146.
110.Vettoretti S, Ochodnicky P, Buikema H, Henning RH, Alex Kluppel C, de Zeeuw D, van Dokkum RPE. Altered myogenic constriction and endothelium-derived hyperpolarizing factor-mediated relaxation in small mesenteric arteries of hypertensive subtotally nephrectomized rats. J Hypertens. 2006;24:2215-2223.
111.Chuah YK, Basir R, Talib H, Tie TH, Nordin N. Receptor for advanced glycation end products and its involvement in inflammatory diseases. Int J Inflam. 2013;2013:403460.
112.Ott C, Jacobs K, Haucke E, Santos AN, Grune T, Simm A. Role of advanced glycation end products in cellular signaling. Redox Biol. 2014;2:411-429.
113.Schäfer N, Lohmann C, Winnik S, van Tits LJ, Miranda MX, Vergopoulos A, Ruschitzka F, Nussberger J, Berger S, Lüscher TF, Verrey F, Matter CM. Endothelial mineralocorticoid receptor activation mediates endothelial dysfunction in diet-induced obesity. Eur Heart J. 2013;34:3515-3524.
114.Adel H, Taye A, Khalifa M. Spironolactone improves endothelial dysfunction in Streptozocin-induced diabetic rats. Naunyn-Schmiedeberg’s Arch Pharmacol. 2014;387:1187-1197.
115.Zhou LL, Cao W, Xie C, Tian J, Zhou Z, Zhou Q, Zhu P, Li A, Liu Y, Miyata T, Hou FF, Nie J. The receptor of adcnaced glycation end products play a central role in advanced oxidation products-induced podocyte apoptosis. Kidney Int. 2012;82:759-770.
116.Forbes JM, Thallas V, Thomas MC, Founds HW, Burns WC, Jerums G, Cooper ME. The breakdown of pre-existing advanced glycation end products is associated with reduced renal fibrosis in experimental diabetes. FASEB J. 2003;17(12):1762-1764.
117.Finkel T, Deng CX, Mostoslavsky R. Recent progress in the biology and physiology of sirtuins. Nature. 2009;460(7255):587-591.
118.Rezaei M, Keshtzar E, Khodayer MJ, Javadipour M. SirT3 regulates diabetogenic effects caused by arsenic: An implication for mitochondrial complex II modification. Toxicol Lett. 2019;301:24-33.
119.Lombard DB, Alt FW, Cheng HL, Bunkenborg J, Streeper RS, Mostoslavsky R, et al. Mammalian Sir2 Homolog SIRT3 regulates global mitochondrial lysine acetylation. Mol Cell Biol. 2007;27(24):8807-8814.
120.Chen Y, Zhang J, Lin Y, Lei Q, Guan KL, Zhao S, Xiong Y. Tumour suppressor SIRT3 deacetylates and activates manganese superoxide dismutase to scavenge ROS. EMBO rep. 2011;12:534-541.
121.Tseng AH, Shieh SS, Wang DL. SIRT3 deacetylates FOXO3 to protect mitochondria against oxidative damage. Free Radic Biol Med. 2013;63:222-234.
122.Ren X, Ren L, Wei Q, Shao H, Chen L, Liu N. Advanced glycation end-peoducts decreases expression of endothelial nitric oxide synthase through oxidative stress in human coronary artery endothelial cells. Cardiovasc Diabetol. 2017;16:52.
123.Zinkevich NS, Gutterman DD. ROS induced ROS release in vascular biology: redox-redox signaling. Am J Physiol Heart Circ Physiol. 2011;301:H647-H653.
124.Montezano AC, Touyz RM. Reactive oxygen species ans endothelial function - role of nitric oxide synthase uncoupling and Nox family nicotinamide adenine dinucleotide phosphate oxidases. Basic Clin Pharmacol Toxicol. 2012;110(1):87-94.
125.Violi F, Sanguigni V, Carnevale R, Plebani A, Rossi P, Finocchi A, et al. Hereditary deficiency of gp91(phox) is associated with enhanced arterial dilatation: results of a multicenter study. Circulation. 2009;120:1616-1622.
126.Taye A, Morawietz H. Spironolactone inhibits NADPH oxidase-induced oxidative stress and enhances eNOS in human endothelial cells. Iran J Pharm Res. 2011;10(2):329-337.
127.Sánchez-Pozos K, Barrera-Chimal J, Garzón-Muvdi J, Pérez-Villalva R, Rodríguez-Romo R, Cruz C, et al. Recovery from ischemic acute kidney injury by spironolactone administration. Nephrol Dial Transplant. 2012;27:3160-3169.
128.Han SY, Kim CH, Kim HS, Jee YH, Song HK, Lee MH, et al. Spironolactone prevents diabetic nephropathy through an anti-inflammatory mechanism in type 2 diabetic rats. J Am Sec Nephrol. 2006;17:1362-1372.