Endothelzellaktivierung bei Diabetes mellitus

A. Bierhaus; M. Andrassy; S. Schiekofer; J. Chen; P. M. Humpert; L. Bai; B. Chen; E. Schleicher; P. P. Nawroth

doi:10.1055/s-0037-1619518

Hämostaseologie, Table of Contents

Hamostaseologie 2001; 21(04): 151-158
DOI: 10.1055/s-0037-1619518

Original article

Schattauer GmbH

Endothelzellaktivierung bei Diabetes mellitus

Endothelial cell activation in diabetes mellitus

A. Bierhaus

¹Medizinische Klinik I, Universität Heidelberg

,

M. Andrassy

¹Medizinische Klinik I, Universität Heidelberg

,

S. Schiekofer

¹Medizinische Klinik I, Universität Heidelberg

,

J. Chen

¹Medizinische Klinik I, Universität Heidelberg

,

P. M. Humpert

¹Medizinische Klinik I, Universität Heidelberg

⁴Deutsches Herzzentrum München, Abt. für experimentelle Kardiologie

,

L. Bai

¹Medizinische Klinik I, Universität Heidelberg

³Chinese Academy of Medical Sciences, Peking Union Medical College, Department of Biochemistry, China

,

B. Chen

³Chinese Academy of Medical Sciences, Peking Union Medical College, Department of Biochemistry, China

,

E. Schleicher

²Medizinische Klinik IV, Universität Tübingen

,

P. P. Nawroth

¹Medizinische Klinik I, Universität Heidelberg

› Author Affiliations

Abstract

Zusammenfassung

Gefäßerkrankungen gelten als eine Hauptursache für die Morbidität und Mortalität von Patienten mit Diabetes mellitus. Klinische Studien zeigen, dass eine intensivierte Blutzuckerkontrolle die Entwicklung vaskulärer Spätschäden deutlich verlangsamt, sodass Hyperglykämie mittlerweile als ein wichtiger Faktor für die Enstehung von Gefäßveränderungen betrachtet wird. Verschiedene durch Hyperglykämie aktivierte Stoffwechselwege wie der Polyolstoffwechselweg, die Aktivierung der Proteinkinase C, die nicht-enzymatische Glykierung von Proteinen und Veränderungen im Redoxpotenzial beeinflussen und verstärken sich dabei gegenseitig. Eine mögliche gemeinsame Endstrecke aller durch Hyperglykämie bedingten zellulären Veränderungen ist die Erzeugung von reaktiven Sauerstoffmolekülen (ROIs) und von oxidativem Stress. Oxidativer Stress aktiviert den Transkriptionsfaktor NF-κB und in Folge die NF-κB-abhängige endotheliale Genexpression, die möglicherweise zur endothelialen Dysfunktion bei Diabetes mellitus beitragen kann.

Summary

Vascular complications are regarded as a main cause for the morbidity and mortality in diabetes mellitus. Clinical studies demonstrate that intensive glycaemic control seems to slow the onset and progression of vascular complications and indicate that hyperglycaemia is one important mediator of endothelial dysfunction. Various pathways as the polyol pathway, activation of protein kinase C, formation of advanced glycation endproducts (AGEs) and changes in the redox potential are supposed to contribute to the adverse effects of hyperglycaemia on the endothelium. A common endpoint of hyperglycaemia dependent cellular changes is the generation of reactive oxygen intermediates (ROIs) and the presence of elevated oxidative stress, that results in activation of the transcription factor NF-κB and alterations in endothelial gene expression that might contribute to endothelial dysfunction in diabetes mellitus.

Schlüsselwörter

Nicht-enzymatische Glykierung - RAGE - oxidativer Stress - NF-κB

Keywords

Advanced glycation endproducts - RAGE - oxidative stress - NF-κB

Full Text

References

Literatur
1 Anrather D, Millan MT, Palmetshofer A. et al. Thrombin activates nuclear factor-kappaB and potentiates endothelial cell activation by TNF. J Immunol 1997; 159: 5620-8.
2 Aso Y, Inukai T, Tayama K. et al. Serum concentrations of advanced glycation endproducts are associated with the development of atherosclerosis as well as diabetic microangiopathy in patients with type 2 diabetes. Acta Diabet 2000; 37: 87-92.
3 Andrews RK, Shen Y, Gardiner EE. et al. The glycoprotein Ib-IX-V-complex in platelet adhesion and signaling. Thromb Haemost 1999; 82: 357-64.
4 Baeuerle PA. Proinflammatory signaling: Last pieces in the NF-κB puzzle?. Current Biology 1998; 8: R19-R22.
5 Baeuerle PA, Baltimore D. NF-κB: ten years after. Cell 1996; 87: 13-20.
6 Baeuerle PA, Henkel T. Function and activation of NF-κB in the immune system. Annu Rev Immun 1994; 12: 141-79.
7 Baynes JW, Thorpe SR. Role of oxidative stress in diabetic complications: a new perspective on an old paradigm. Diabetes 1999; 48: 1-9.
8 Baynes JW, Thorpe SR. Glycoxidation and lipoxidation in atherogenesis. Free Radic Biol Med 2000; 28: 1708-16.
9 Barnes PJ, Karin M. Nuclear Factor-κB – a pivotal transcription factor in chronic inflammatory diseases. N Engl J Med 1997; 336: 1066-71.
10 Barouch FC, Miyamoto K, Allport JR. et al. Integrin-mediated neutrophil adhesion and retinal leukostasis in diabetes. Invest Ophthalmol Vis Sci 2000; 41: 1153-8.
11 Bevilacqua MP, Stengelin S, Gimbrone MA. et al. Endothelial leukocyte adhesion molecule 1: an inducible receptor for neutrophils related to complement regulatory proteins and lectins. Science 1989; 243: 1160-5.
12 Bierhaus A, Zhang Y, Deng Y. et al. Mechanism of the TNFα mediated induction of endothelial tissue factor. J Biol Chem 1995; 270: 26419-32.
13 Bierhaus A, Chevion S, Chevion M. et al. Advanced glycation endproducts (AGEs) induced activation of NF-κB is suppressed by α-lipoic acid in cultured endothelial cells. Diabetes 1997; 46: 1481-90.
14 Bierhaus A, Illmer T, Kasper M. et al. Advanced glycation end product (AGE)-mediated induction of tissue factor in cultured endothelial cells is dependent on RAGE. Circulation 1997; 96: 2262-71.
15 Bierhaus A, Ziegler R, Nawroth PP. Molecular mechanisms of diabetic angiopathy – clues for innovative therapeutic interventions. Horm Res 1998; 50 (Suppl. 01) 1-5.
16 Bierhaus A, Hofmann MA, Ziegler R. et al. The AGE/RAGE pathway in vascular disease and diabetes mellitus. Part I: The AGE-concept. Cardiovasc Res 1998; 37: 586-600.
17 Bierhaus A, Chen J, Liliensiek B, Nawroth PP. LPS and cytokine activated endothelium. Sem Thromb Hemost 2000; 26: 571-87.
18 Bierhaus A, Schiekofer S, Schwaninger M. et al. Diabetes-associated sustained activation of the transcription factor NF-κB. Diabetes. (in press).
19 Boeri D, Almus FE, Maiello M. et al. Modification of tissue factor mRNA and protein response to thrombin and interleukin 1 by high glucose in cultured human endothelial cells. 1989; 38: 212-8.
20 Borcea V, Nourooz-Zadeh J, Wolff SP. et al. alpha-Lipoic acid decreases oxidative stress even in diabetic patients with poor glycemic control and albuminuria. Free Radic Biol Med 1999; 26: 1495-500.
21 Bursell SE, King GL. Can protein kinase C inhibition and vitamin E prevent the development of diabetic vascular complications?. Diabetes Res Clin Pract 1999; 45: 169-82.
22 Cameron NE, Cotter MA. Metabolic and vascular factors in the pathogenesis of diabetic neuropathy. Diabetes 1997; 46 (Suppl. 02) S31-7.
23 Cavallo-Perin P, Lupia E, Gruden G. et al. Increased blood levels of platelet-activating factor in insulin-dependent diabetic patients with microalbuminuria. Nephrol Dial Transplant 2000; 15: 994-9.
24 Carr ME. Diabetes mellitus: a hypercoagulable state. J Diabetes Complications 2001; 15: 44-54.
25 Ceriello A, Marchi E, Barbanti M. et al. Nonenzymatic glycation reduces heparin cofactor II anti-thrombin activity. Diabetologia 1990; 33: 205-7.
26 Collins T, Cybulsky MI. NF-κB: pivotal mediator or innocent bystander in atherogenesis?. J Clin Invest 2001; 107: 255-64.
27 Collins T, Read M, Neish A. et al. Transcriptional regulation of endothelial adhesion molecules: NF-κB and cytokine-inducible enhancers. FASEB J 1995; 9: 899-909.
28 De Vriese AS, Verbeuren TJ, Van de Voorde J. et al. Endothelial dysfunction in diabetes. Br J Pharmacol 2000; 130: 963-74.
29 Deprés JP, Lamarché B, Mauriège P. et al. Hyperinsulinemia as an independent risk factor for ischemic heart disease. N Engl J Med 1996; 334: 952-7.
30 Di Mario U, Pugliese G. 15^th Golgi lecture: from hyperglycaemia to the dysregulation of vascular remodelling in diabetes. Diabetologia 2001; 44: 674-92.
31 Dosquet C, Weill D, Wautier JL. Molecular mechanism of blood monocyte adhesion to vascular endothelial cells. Nouv Rev Fr Hematol 1992; 34: S55-9.
32 Du XL, Edelstein D, Rossetti L. et al. Hyperglycemia-induced mitochondrial superoxide overproduction activates the hexosamine pathway and induces plasminogen activator inhibitor-1 expression by increasing SP-1 glycosylation. Proc Natl Acad Sci USA 2000; 97: 12222-6.
33 Dunlop M. Aldose reductase and the role of polyol pathway in diabetic nephropathy. Kidney int 2000; 58: S3-12.
34 Du XL, Sui GZ, Stockklauser-Farber K. et al. Introduction of apoptosis by high proinsulin and glucose in cultured human umbilical vein endothelial cells is mediated by reactive oxygen species. Diabetologia 1998; 41: 249-56.
35 Elhadd TA, Kennedy G, Hill A. et al. Abnormal markers of endothelial cell activation and oxidative stress in children, adolescents and young adults with type 1 diabetes with no clinical vascular disease. Diabetes Metab Res Rev 1999; 15: 405-11.
36 Elices M, Osborn L, Takada Y. et al. VCAM-1 on activated endothelium interacts with the leukocyte integrin VLA-4 at a site distinct from the VLA-4 fibronectin binding site. Cell 1990; 60: 577-84.
37 Endo M, Yanagisawa K, Tsuchida K. et al. Increased levels of vascular endothelial growth factor and advanced glycation endproducts in aqueous humor of patients with diabetic retinopathy. Horm Metab Res 2001; 33: 317-22.
38 Esposito C, Gerlach H, Brett J. et al. Endothelial receptor-mediated binding of glucose-modified albumin is associated with increased monolayer permeability and modulation of cell surface coagulant properties. J Exp Med 1989; 170: 1387-407.
39 Fenner E, King GL. Vascular dysfunction in diabetes mellitus. Lancet 1997; 350 (Suppl. 01) 9-13.
40 Garcia Soriano F, Virag L. et al. Diabetic endothelial dysfunction: the role of poly(ADP-ribose) polymerase activation. Nat Med 2001; 7: 108-13.
41 Giuglianu D, Ceriello A. Oxidative stress and diabetic vascular complications. Diabetes Care 1996; 19: 257-67.
42 Godin DV, Wohaieb SA, Garnett ME. et al. Antioxidant enzyme alterations in experimental and clinical diabetes. Mol Cell Biochem 1988; 84: 223-31.
43 Gorlach A, Brandes RP, Bassus S. et al. Oxidative stress and expression of p22phox are involved in the up-regulation of tissue factor in vascular smooth muscle cells in response to activated platelets. FASEB J 2000; 14: 1518-28.
44 Golovchenko I, Goalstone ML, Watson P. et al. Hyperinsulinemia enhances transcriptional activity of nuclear factor κB induced by angiotensin II, hyperglycemia and advanced glycation endproducts in vascular smooth muscle cells. Circ Res 2000; 87: 746-52.
45 Halliwell B. The role of oxygen radicals in human disease, with particular reference to the vascular system. Haemostasis 1993; 23 (Suppl. 01) 118-26.
46 Hammes H-P, Martin S, Federlin K. et al. Aminoguanidine inhibits the development of experimental diabetic retinopathy. Proc Natl Acad Sci USA 1991; 88: 11555-8.
47 Hammes HP, Bartmann A, Engel L. et al. Antioxidant treatment of experimental diabetic retinopathy in rats with nicanartine. Diabetologia 1997; 40: 629-34.
48 Hammes HP, Alt A, Niwa T. et al. Differential accumulation of advanced glycation endproducts in the course of diabetic retinopathy. Diabetologia 1999; 42: 728-36.
49 Hammes HP, Brownlee M, Lin J. et al. Diabetic retinopathy risk correlates with intracellular concentration of the glycoxidation product N-epsilon-(carboxy-methyl)-lysine independently of glycohaemoglobin concentrations. Diabetologia 1999; 42: 603-7.
50 Henn V, Slupsky JR, Grafe M. et al. CD40 ligand on activated platelets triggers an inflammatory reaction in endothelial cells. Nature 1998; 391: 591-4.
51 Hofmann MA, Schiekofer S, Kanitz M. et al. Insufficient glycemic control increases NF-κB binding activity in peripheral blood mononuclear cells isolated from patients with diabetes mellitus. Diabetes Care 1998; 21: 1310-61.
52 Hofmann MA, Schiekofer S, Klevesath MS. et al. Peripheral blood mononuclear cells isolated from patients with diabetic nephropathy demonstrate increased activation of the oxidative-stress sensitive transcription factor NF-κB. Diabetologia 1999; 42: 222-32.
53 Hollenbaugh D, Mischel Petty N, Edwards CP. et al. Expression of functional CD40 by vascular endothelial cells. J Ex Med 1995; 182: 33-40.
54 Hori O, Yan SD, Ogawa S. et al. The receptor for advanced glycation end-products has a central role in mediating the effects of advanced glycation end-products on the development of vascular disease in diabetes mellitus. Nephrol Dial Transplant 1996; 11 (Suppl. 05) 13-6.
55 Hsueh WA, Lau RE. Diabetes is a vascular disease. J Invest Med 1998; 46: 387-90.
56 Hunt JV, Dean RT, Wolff SP. Hydroxyl radical production and autoxidative glycosylation: glucose autoxidation as the cause of protein damage in the experimental glycation model of diabetes and aging. Biochem J 1988; 256: 205-12.
57 Idris I, Gray S, Donnelly R. Protein kinase C activation: isoforme-specific effects on metabolism and cardiovascular complications in diabetes. Diabetologia 2001; 44: 659-73.
58 Inogouchi T, Li P, Umeda F. et al. High glucose level and free fatty acid stimulate reactive oxygen species production through protein C-dependent activation of NAD(P)H oxidase in cultured vascular cells. Diabetes 2000; 49: 1939-49.
59 Introna M, Mantovani A. Early activation signals in endothelial cells – stimulation by cytokines. Arterioscler Thromb Vasc Biol 1997; 17: 423-8.
60 Ishii H, Jirousek MR, Koya D. et al. Amelioration of vascular dysfunction in diabetic rats by an oral PKC-β inhibitor. Science 1996; 272: 728-31.
61 Kiuchi K, Nejima J, Takano T. et al. Increased serum concentration of advanced glycation end products: a marker of coronary atery disease activity in type 2 diabetes patients. Heart 2001; 85: 87-91.
62 King GL, Brownlee M. The cellular and molecular mechanisms of diabetic complications. Endocrin and Metabol 1996; 25: 255-70.
63 Kislinger T, Fu C, Huber B. et al. N^e-(carboxymethyl)lysine adducts of proteins are ligands for receptor for advanced glycation end products that activate cell signaling pathways and modulate gene expression. J Biol Chem 1999; 274: 31740-9.
64 Kislinger T, Tanji N, Wendt T. et al. Receptor for advanced glycation end products mediates inflammation and enhanced expression of tissue factor in vasculature of diabetic apolipoprotein-E-null mice. Arterioskler Thromb Vasc Biol 2001; 21: 905-10.
65 Khechai F, Ollivier V, Bridey F. et al. Effect of advanced glycation end product-modified albumin on tissue factor expression by monocytes. Role of oxidant stress and protein tyrosine kinase activation. Arterioscl Thromb Vasc Biol 1997; 17: 2885-90.
66 Kolm-Litty V, Tippmer S, Haering HU. et al. Glucosamine induces translocation of protein kinase C isoenzymes in mesangial cells. Exp Clin Endocrinol Diabetes 1998; 106: 377-83.
67 Koltai M, Hosford D, Braqut P. Role of PAF and cytokines in microvascular tissue injury. J Lab Clin Med 1992; 119: 461-6.
68 Koya D, King GL. Protein kinase C activation and the development of diabetic complications. Diabetes 1998; 47: 859-66.
69 Krishnaswamy G, Kelley J, Yerra L. et al. Human endothelium as a source of multifunctional cytokines: molecular regulation and possible role in human disease. J Interferon Cytokin Res 1999; 19: 91-104.
70 Kubo E, Nakamura S, Tsuzuki S. et al. Inhibitory effect of orally administered aldose reductase inhibitor SNK-860 on corneal polyol accumulation in galactose-fed rats. Graefes Arch Clin Exp Ophthalmol 1999; 237: 758-62.
71 Kunt T, Forst T, Wilhelm A. et al. Alpha-lipoic acid reduces expression of vascular cell adhesion molecule-1 and endothelial adhesion of human monocytes after stimulation with advanced glycation end products. Clin Sci (Lond) 1999; 96: 75-82.
72 Lander HM, Tauras JM, Ogiste JS. et al. Activation of the receptor for advanced glycation end products triggers a p21(ras)-dependent mitogen-activated protein kinase pathway regulated by oxidant stress. J Biol Chem 1997; 272: 17810-4.
73 Li YM, Steffes M, Donnelly T. et al. Prevention of cardiovascular and renal pathology of aging by the advanced glycation inhibitor amino-guanidine. Proc Natl Acad Sci USA 1996; 93: 3902-7.
74 Li J, Schmidt AM. Characterization and functional analysis of the promoter of RAGE, the receptor for advanced glycation end products. J Biol Chem 1997; 272: 16498-506.
75 Lindsay RM, Jamieson WS, Walker SA. et al. Tissue ascorbic acid and polyol pathway metabolism in experimental diabetes. Diabetologia 1998; 41: 516-23.
76 Lipinski B. Pathophysiology of oxidative stress in diabetes mellitus. J Diabetes Complications 2001; 15: 203-10.
77 Mantovani A, Bussolino F, Dejana E. Cytokine regulation of endothelial cell function. FASEB J 1992; 6: 2591-9.
78 May AE, Neumann FJ, Preissner KT. The relevance of blood cell-vessel wall adhesive interactions for vascular thrombotic disease. Thromb Haemost 1999; 82: 962-70.
79 Miller DL, Yaron R, Yellin MJ. CD40L-CD40 interactions regulate endothelial cell surface tissue factor and thrombomodulin. J Leukoc Biol 1998; 63: 373-9.
80 Morigi M, Angioletti S, Imberti B. et al. Leukocyte-endothelial interaction is augmented by high glucose concentrations and hyperglycemia in a NF-κB-dependent fashion. J Clin Invest 1998; 101: 1905-15.
81 Morcos M, Borcea V, Isermann B. et al. Effect of alpha-lipoic acid on the progression of endothelial cell damage and albuminuria in patients with diabetes mellitus: an exploratory study. Diabetes Res Clin Pract 2001; 52: 175-83.
82 Nakamura N, Obayashi H, Fujii M. et al. Induction of aldose reductase in cultured human microvascular endothelial cells by advanced glycation end products. Free Radic Biol Med 2000; 29: 17-25.
83 Nawroth PP, Bank I, Handley D. et al. Tumor necrosis factor/-cachectin interacts with endothelial cell receptors to induce release of interleukin-1. J Ex Med 1986; 163: 1363-75.
84 Nawroth PP, Stern DM. Modulation of endothelial cell hemostatic properties by tumor necrosis factor. J Exp Med 1986; 163: 740-5.
85 Nawroth PP, Bierhaus A, Vogel GE. et al. Nicht-enzymatische Glykierung und oxidativer Stress bei chronischen Erkrankungen und Diabetes mellitus. Med Klinik 1999; 94: 29-38.
86 Nishikawa T, Edelstein D, Brownlee M. The missing link: a single unifying mechanism for diabetic complications. Kidney Int 2000; 58 (Suppl. 77) S26-30.
87 Nishikawa T, Edelstein D, Du XL. et al. Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage. Nature 2000; 404: 787-90.
88 Nourooz-Zadeh J, Tajaddini-Sarmadi J, McCarthy S. et al. Elevated levels of authentic plasma hydroperoxides in NIDDM. Diabetes 1995; 44: 1054-8.
89 Nourooz-Zadeh J, Rahimi A, Tajaddini-Sarmadi J. et al. Relationships between plasma measures of oxidative stress and metabolic control in NIDDM. Diabetologia 1997; 40: 647-53.
90 Parry GC, Mackman N. Transcriptional regulation of tissue factor expression in human endothelial cells. Arterioscler Thromb Vasc Biol 1995; 15: 612-21.
91 Porte D, Schwartz MW. Diabetes complications: why is glucose potentially toxic. Science 1996; 272: 699-700.
92 Quehenberger P, Bierhaus A, Fasching P. et al. Endothelin 1 transcription is controlled by nuclear factor-kappa B in AGE-stimulated cultured endothelial cells. Diabetes 2000; 49: 1561-70.
93 Read MA, Whitley MZ, Williams AJ. et al. NF-kappa B and I kappa B alpha: an inducible regulatory system in endothelial activation. J Exp Med 1994; 179: 503-12.
94 Rigla M, Mateo J, Fontcuberta J. et al. Normalisation of tissue factor pathway inhibitor activity after glycaemic control optimisation in type 1 diabetic patients. Thromb Haemost 2000; 84: 223-7.
95 Schaffler A, Arndt H, Scholmerich J. et al. Amelioration of hyperglycemic and hyper-osmotic induced vascular dysfunction by in vivo inhibition of protein kinase C and p38 MAPkinase pathway in the rat mesenteric microcirculation. Eur J Clin Invest 2000; 30: 586-93.
96 Schiekofer S, Balletshofer B, Andrassy M. et al. Endothelial dysfunction in diabetes mellitus. Sem Thromb Hemost 2000; 26: 503-12.
97 Schleicher ED, Wagner E, Nerlich AG. Increased accumulation of the glycoxidation product Ne-(carboxymethyl)lysine in human tissues in diabetes and aging. J Clin Invest 1997; 99: 457-68.
98 Schleicher ED, Weigert C. Rolle of the hexosamine biosynthetic pathway in diabetic nephropathy. Kidney Int 2000; 58 (Suppl. 77) S13-8.
99 Schmidt AM, Yan SD, Stern DM. The dark side of glucose. Nature Med 1995; 1: 1002-4.
100 Schmidt AM, Hori O, Chen JX. et al. Advanced glycation endproducts interacting with their endothelial receptor induce expression of vascular cell adhesion molecule-1 (VCAM-1) in cultured human endothelial cells and in mice. A potential mechanism for the accelerated vasculopathy of diabetes. J Clin Invest 1995; 96: 1395-403.
101 Schmidt AM, Yan SD, Wautier JL. et al. Activation of receptors for advanced glycation end products: a mechanism for chronic vascular dysfunction in diabetic vasculopathy and atherosclerosis. Circ Res 1999; 84: 489-97.
102 Schmidt AM, Hofmann M, Taguchi A. et al. RAGE: a multiligand receptor contributing to the cellular response in diabetic vasculopathy and inflammation. Sem Thromb Hemost 2000; 26: 485-94.
103 Schmidt AM, Yan SD, Yan SF. et al. The biology of the receptor for advanced glycation end products and its ligands. Biochim Biophys Acta 2000; 1498: 99-111.
104 Schmidt AM, Stern D. Hyperinsulinemia and vascular dysfunction: the role of nuclear factor-kappa B, yet again. Circ Res 2000; 87: 722-4.
105 Schmidt AM, Stern D. A radical approach to the pathogenesis of diabetic complications. Trends Pharmacol Sci 2000; 21: 367-9.
106 Sellers DJ, Chess-Williams R. The effect of sorbinil, an aldose reductase inhibitor, on aortic function in control and streptozotocininduced diabetic rats. J Auton Pharmacol 2000; 20: 15-22.
107 Sowers JR, Epstein M, Frohlich ED. Diabetes, hypertension, and cardiovascular disease: an update. Hypertension 2001; 37: 1053-9.
108 Spanheimer RG. Reducing cardiovascular risk in diabetes. Which factors to modify first?. Postgrad Med 2001; 109: 26-30 33-6.
109 Standl E. Cardiovascular risk in type 2 diabetes. Diabetes Obes Metab 1999; (Suppl. 02) S24-36.
110 Stehouwer CD, Schaper NC. The pathogenesis of vascular complications of diabetes mellitus: one voice or many?. Eur J Clin Invest 1996; 26: 535-43.
111 Stern DM, Bank I, Nawroth PP. et al. Self-regulation of procoagulant events on the endothelial cell surface. J Ex Med 1985; 162: 1223-35.
112 Thurberg BL, Collins T. The nuclear factor-kB/inhibitor of kappa B autoregulatory system and atherosclerosis. Current Opin Lipid 1998; 9: 387-96.
113 Ting HH, Timimi FK, Boles KS. et al. Vitamin C improves endothelium-dependent vasodilatation in patients with non-insulin dependent diabetes mellitus. J Clin Invest 1996; 97: 22-8.
114 Vlassara H, Bucala R, Striker L. Pathogenetic effects of advanced glycosylation: biochemical, biologic and clinical implications for diabetes and aging. Lab Invest 1994; 70: 138-11.
115 Vlassara H. Advanced glycation end-products and atherosclerosis. Ann Med 1996; 28: 419-26.
116 Wautier JL, Zoukourian C, Chappey O. et al. Receptor-mediated endothelial cell dysfunction in diabetic vasculopathy. Soluble receptor for advanced glycation end products blocks hyperpermeability in diabetic rats. J Clin Invest 1996; 96: 238-43.
117 Wautier MP, Chappey O, Corda S. et al. Activation of NADPH oxidase by RAGE links oxidant stress to altered gene expression via RAGE. Am J Physiol Endocrinol Metab 2001; 280: E685-94.
118 Wells-Knecht KJ, Zyzak DV, Litchfield JE. et al. Mechanism of autoxidative glycosylation: identification of glyoxal and arabinose as intermediates in the autoxidative modification of proteins by glucose. Biochemistry 1995; 34: 3702-9.
119 Williamson JR, Chang K, Frangos M. et al. Hyperglycemic pseudohypoxia and diabetic complications. Diabetes 1993; 42: 801-13.
120 Wolfenbuettel BHR, Boulanger CM. et al. Breakers of advanced glycation end products restore large artery properties in experimental diabetes. Proc Natl Acad Sci USA 1992; 95: 11555-8.
121 Yokoyama H, Myrup B, Rossing P. et al. Increased tissue factor pathway inhibitor activity in IDDM patients with nephropathy. Diabetes Care 196 (29) 441-5.
122 Zabel U, Henkel T, Sila MS. et al. Nuclear uptake control of NF-κB by MAD-3, an I kappa B protein present in the nucleus. EMBO J 1993; 12: 201-11.
123 Zumbach M, Hofmann M, Borcea V. et al. Tissue factor antigen is elevated in patients with microvascular complications of diabetes mellitus. Exp Clin Endocrinol Diabetes 1997; 105: 206-12.