Zusammenfassung
Lebensstil bzw. Ernährungsgewohnheiten können Ursache von „nutritivem” Stress sein. Wird unter derartigen Bedingungen die Oxidationskapazität der Mitochondrien überschritten, kommt es zur mitochondrialen Generation von Superoxidanionen. Als weitere Quellen der Bildung von reaktiven Sauerstoffspezies wurden die Stickstoffmonoxidsynthase (NOS) und die NADPH-Oxidasen in Gefäßzellen und intakten Gefäßen identifiziert. Wir vermuten, dass im Diabetes die mitochondriale Generation von reaktiven Sauerstoffspezies „katalytischen” Charakter hat und über die Entkoppelung des Elektronenflusses im NOS-Komplex und die Aktivierung des Angiotensinsystems als Verstärkungsmechanismen oxidativen Stress erzeugt. Dieser ist einerseits Ursache für die endotheliale Dysfunktion, die einen initialen Schritt bei der Entstehung mikro- und makroangiopathischer Gefäßkomplikationen darstellt. Wichtige Faktoren hierbei sind die verminderte Bioverfügbarkeit von Stickstoffmonoxid, die Aktivierung redoxsensitiver Transkriptionsfaktoren (NFκB und AP-1) sowie die direkte oxidative Schädigung der genomischen und mitochondriellen DNA. Andererseits kann der oxidative Stress auch Ursache für die Entstehung einer Insulinresistenz und eines Typ-2-Diabetes sein, Prozesse, die zur Verstärkung des oxidativen Stresses und damit wiederum zum Entstehen einer endothelialen Dysfunktion beitragen.
Abstract
Life style and nutritional behaviour may cause „nutritive stress”. Under conditions of nutritive stress, if substrate flow exceeds the capacity of mitochondrial oxidation, super oxide anions are generated by mitochondria. As additional sources of reactive oxygen species nitric oxide synthase (NOS) as well as NADPH oxidase have been identified in diabetic vessels and vascular cells. We suggest that the mitochondrial generation of reactive oxygen species leads to an uncoupling of the electron flow in the NOS complex and to an activation of the angiotensin system. Both processes amplify the generation of reactive oxygen species leading to oxidative stress. It is known that oxidative stress disturbs and impairs various endothelial functions and may establish endothelial dysfunction which is an initial and causative factor for development of micro- and macroangiopathic complications. The reduced bioavailability of nitric oxide, activation of redox-sensitive transcription factors such NFκB and AP-1 and direct damage of genomic and mitochondrial DNA are important mechanisms. On the other hand, there is some evidence that oxidative stress may also be the cause for development of insulin resistance and type 2 diabetes. Both processes may accelerate and aggravate the development of endothelial dysfunction in diabetes.
Schlüsselwörter
Endothel - Insulinresistenz - Diabetes mellitus - reaktive Sauerstoffspezies - oxidativer Stress - Angiotensin II - Mikro- und Makroangiopathie
Key words
Endothelium - diabetes mellitus - reactive oxygen species - oxidative stress - angiotensin II - microangiopathy and macroangiopathy
Literatur
-
1
Zimmet P, Alberti K G, Shaw J.
Global and societal implications of the diabetes epidemic.
Nature.
2001;
414
782-787
-
2
Haffner S M, Lehto S, Ronnemaa T, Pyorala K, Laakso M.
Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction.
N Engl J Med.
1998;
339
229-234
-
3
Stamler J, Vaccaro O, Neaton J D, Wentworth D.
Diabetes, other risk factors, and 12-year cardiovascular mortality for men screened in the Multiple Risk Factor Intervention Trial.
Diabetes Care.
1993;
16
434-444
-
4
Pinkney J H, Stehouwer C D, Coppack S W, Yudkin J S.
Endothelial dysfunction: cause of the insulin resistance syndrome.
Diabetes.
1997;
46, Suppl 2
S9-13
-
5
Uusitupa M I, Niskanen L K, Siitonen O, Voutilainen E, Pyorala K.
Ten-year cardiovascular mortality in relation to risk factors and abnormalities in lipoprotein composition in type 2 (non-insulin-dependent) diabetic and non-diabetic subjects.
Diabetologia.
1993;
36
1175-1184
-
6 Gimbrone A, Topper J N. Biology of the vessel wall: endothelium. Molecular Basis of Cardiovascular Disease. Edited by Chien KR. Philadelphia; W. B. Saunders Company 1999: 331-348
-
7
Baumgartner-Parzer S M, Waldhäusl W K.
The endothelium as a metabolic and endocrine organ: its relation with insulin resistance.
Exp Clin Endocrinol Diabetes.
2001;
109 Suppl 2
S166-S179
-
8
Brownlee M.
Biochemistry and molecular cell biology of diabetic complications.
Nature.
2001;
414
813-820
-
9
Ross R, Glomset J A.
The pathogenesis of atherosclerosis (second of two parts).
N Engl J Med.
1976;
295
420-425
-
10
Ross R, Glomset J A.
The pathogenesis of atherosclerosis (first of two parts).
N Engl J Med.
1976;
295
369-377
-
11 Gimbrone M A. Endothelial dysfunction and the pathogenesis of atherosclerosis. Atherosclerosis VII, Proceedings of the 7th Int. Symp. on Atherosclerosis. Edited by Fidge NH and Nestel PJ. Amsterdam; Exerpat Medica 1986: 367-369
-
12
Rösen P.
Endotheliale Dysfunktion: ein Synonym für funktionelle Atherosklerose.
J Kardiol.
2002;
9
556-562
-
13 Rösen P. Biochemie der Folgeerkrankungen des Diabetes mellitus: Hyperglykämie als Ursache vaskulärer Komplikationen. In: Waldhäusl W, Gries FA, Scherbaum W (eds) Diabetes in der Praxis. Stuttgart; Thieme Verlag 2002
-
14
Schächinger V, Zeiher A M.
Quantitative assessment of coronary vasoreactivity in humans in vivo. Importance of baseline vasomotor tone in atherosclerosis.
Circulation.
1995;
92
2087-2094
-
15
Meredith I A, Yeung A C, Weidinger F F.
Role of impaired endothelium dependent vasodilation in schemic manifestations of coronary artery disease.
Circulation.
1993;
87 (Suppl V)
S56-S66
-
16
Nabel E G, Selwyn A P, Ganz P.
Large coronary arteries in humans are responsive to changing blood flow: an endothelium-dependent mechanism that fails in patients with atherosclerosis.
J Am Coll Cardiol.
1990;
16
349-356
-
17
Taylor A A.
Pathophysiology of hypertension and endothelial dysfunction in patients with diabetes mellitus.
Endocrinol Metabol Clin North Am Pract.
2001;
30
983-997
-
18
Bell D S.
Inflammation, insulin resistance, infection, and atherosclerosis.
Endocr Pract.
2000;
6
272-276
-
19
Creager M A, Cooke J P, Mendelsohn M E, Gallagher S J, Coleman S M, Loscalzo J, Dzau V J.
Impaired vasodilation of forearm resistance vessels in hypercholesterolemic humans.
J Clin Invest.
1990;
86
228-234
-
20
Moncada S.
Nitric oxide.
Hypertension.
1994;
12
35-39
-
21
Schächinger V, Britten M B, Zeiher A M.
Prognostic impact of coronary vasodilator dysfunction on adverse long-term outcome of coronary heart disease.
Circulation.
2000;
101
1899-1906
-
22
Steinberg H O, Baron A D, Steinberg H. et al .
Vascular function, insulin resistance and fatty acids.
Diabetologia.
2002;
45
623-634
-
23
Williams S B, Goldfine A B, Timimi F K, Ting H H, Roddy M A, Simonson D C, Creager M A.
Acute hyperglycemia attenuates endothelium-dependent vasodilation in humans in vivo.
Circulation.
1998;
97
1695
-
24
Ceriello A.
New insights on oxidative stress and diabetic complications may lead to a „Causal” antioxidant therapy.
Diabetes Care.
2003;
26
1589-1596
-
25
Perticone F.
Post-prandial hypertriglyceridemia and endothelium-dependent vasorelaxation.
Eur J Clin Invest.
2001;
31
1013-1014
-
26
Balletshofer B M, Rittig K, Enderle M D, Volk A, Maerker E, Jacob S, Matthaei S, Rett K, Haring H U.
Endothelial dysfunction is detectable in young normotensive first-degree relatives of subjects with type 2 diabetes in association with insulin resistance.
Circulation.
2000;
101
1780-1784
-
27
Jagasia D, Whiting J M, Concato J, Pfau S, McNulty P H.
Effect of non-insulin-dependent diabetes mellitus on myocardial insulin responsiveness in patients with ischemic heart disease.
Circ.
2001;
103
1734-1739
-
28
Stehouwer C D, Gal M AI, Twisk J W, Knudsen E, Emeis J J, Parving H H.
Increased urinary albumin excretion, endothelial dysfunction, and chronic low-grade inflammation in type 2 diabetes: progressive, interrelated, and independently associated with risk of death.
Diabetes.
2002;
51
1157-1165
-
29
Ting H H, Timimi F K, Boles K S, Creager S J, Ganz P, Creager M A.
Vitamin C improves endothelium-dependent vasodilation in patients with non-insulin-dependent diabetes mellitus.
J Clin Invest.
1996;
97 (1)
22-28
-
30
Ting H H, Timimi F K, Haley E A, Roddy M A, Ganz P, Creager M A.
Vitamin C improves endothelium-dependent vasodilation in forearm resistance vessels of humans with hypercholesterolemia.
Circulation.
1997;
95 (12)
2617-2622
-
31
Hornig B, Arakawa N, Kohler C, Drexler H.
Vitamin C improves endothelial function of conduit arteries in patients with chronic heart failure.
Circulation.
1998;
97 (4)
363-368
-
32
Gokce N, Keaney J F, Frei B, Holbrook M, Olesiak M, Zachariah B J, Leeuwenburgh C, Heinecke J W, Vita J A.
Long-term ascorbic acid administration reverses endothelial vasomotor dysfunction in patients with coronary artery disease.
Circulation.
1999;
99 (25)
3234-3240
-
33
Taddei S, Virdis A, Ghiadoni L, Magagna A, Salvetti A.
Vitamin C improves endothelium-dependent vasodilation by restoring nitric oxide activity in essential hypertension.
Circulation.
1998;
97 (22)
2222-2229
-
34
Motoyama T, Kawano H, Kugiyama K, Hirashima O, Ohgushi M, Yoshimura M, Ogawa H, Yasue H.
Endothelium-dependent vasodilation in the brachial artery is impaired in smokers: effect of vitamin C.
Am J Physiol.
1997;
273 (4 Pt 2)
H1644-H1650
-
35
Rösen P, Nawroth P, King G L, Tritschler H J, Packer L.
The role of oxidative stress in the onset and progression of diabetes and its complications.
Diabetes/Metabolism Res Rev.
2001;
17
189-212.
-
36
Du X, Stocklauser-Färber K, Rösen P.
Generation of reactive oxygen intermediates, activation of NF-κB, and induction of apoptosis in human endothelial cells by glucose: role of nitric oxide synthase?.
Free Radic Biol Med.
1999;
27
752-763
-
37 Rösen P, Du X L. Oxidative stress in diabetes: why does hyperglycaemia induce the formation of reactive oxygen species?. In: Packer L, Rösen P, Tritschler HJ, King GL, Azzi A (eds) Antioxidants in Diabetes Management. New York; Marcel Dekker 2000: 17-32
-
38
Davi G, Ciabattoni G, Consoli A, Mezzetti A, Falco A, Santarone S, Pennese E, Vitacolonna E, Bucciarelli T, Costantini F, Capani F, Patrono C.
In vivo formation of 8-iso-prostaglandin F2α and platelet activation in diabetes mellitus: effects of improved metabolic control and vitamin E supplementation.
Circulation.
1999;
99
224-229
-
39
Yan S D, Schmidt A M, Anderson G M, Zhang J, Brett J, Zou Y S, Pinsky D, Stern D.
Enhanced cellular oxidant stress by the interaction of advanced glycation end products with their receptors/binding proteins.
J Biol Chem.
1994;
269
9889-9897
-
40
Lee H S, Son S M, Kim Y K, Hong K W, Kim C D.
NAD(P)H oxidase participates in the signaling events in high glucose-induced proliferation of vascular smooth muscle cells.
Life Sci.
2003;
72
2719-2730
-
41
Baker T A, Milstien S, Katusic Z S.
Effect of vitamin C on the availability of tetrahydrobiopterin in human endothelial cells.
J Cardiovasc Pharmacol.
2001;
37 (3)
333-338
-
42
d'Uscio L V, Milstien S, Richardson D, Smith L, Katusic Z S.
Long-term vitamin C treatment increases vascular tetrahydrobiopterin levels and nitric oxide synthase activity.
Circ Res.
2003;
92 (1)
88-95
-
43
Wong R K, Pettit A I, Davies J E, Ng L L.
Augmentation of the neutrophil respiratory burst through the action of advanced glycation end products: a potential contributor to vascular oxidant stress.
Diabetes.
2002;
51
2846-2853
-
44
Wautier M P, Chappey O, Corda S, Stern D M, Schmidt A M, Wautier J L.
Activation of NADPH oxidase by AGE links oxidant stress to altered gene expression via RAGE.
Am J Physiol Endocrinol Metab.
2001;
280
E685-E694
-
45
Inoguchi T, Li P, Umeda F, Yu H Y, Kakimoto M, Imamura M, Aoki T, Etoh T, Hashimoto T, Naruse M, Sano H, Utsumi H, Nawata H.
High glucose level and free fatty acid stimulate reactive oxygen species production through protein kinase C-dependent activation of NAD(P)H oxidase in cultured vascular cells.
Diabetes.
2000;
49
1939-1945
-
46
Matsunaga T, Nakajima T, Miyazaki T, Koyama I, Hokari S, Inoue I, Kawai S, Shimomura H, Katayama S, Hara A, Komoda T.
Glycated high-density lipoprotein regulates reactive oxygen species and reactive nitrogen species in endothelial cells.
Metabolism.
2003;
52
42-49
-
47
Nickenig G, Harrison D G.
The AT(1)-type angiotensin receptor in oxidative stress and atherogenesis: part I: oxidative stress and atherogenesis.
Circulation.
2002;
105
393-396
-
48
Warnholtz A, Nickenig G, Schulz E, Macharzina R, Brasen J H, Skatchkov M, Heitzer T, Stasch J P, Griendling K K, Harrison D G, Bohm M, Meinertz T, Munzel T.
Increased NADH-oxidase-mediated superoxide production in the early stages of atherosclerosis: evidence for involvement of the renin-angiotensin system.
Circulation.
1999;
99
2027-2033
-
49
Lonn E, Yusuf S, Hoogwerf B, Pogue J, Yi Q, Zinman B, Bosch J, Dagenais G, Mann J F, Gerstein H C.
Effects of vitamin E on cardiovascular and microvascular outcomes in high-risk patients with diabetes: results of the HOPE study and MICRO-HOPE substudy.
Diabetes Care.
2002;
25
1919-1927
-
50
Gerstein H C.
Reduction of cardiovascular events and microvascular complications in diabetes with ACE inhibitor treatment: HOPE and MICRO-HOPE.
Diabetes Metab Res Rev.
2002;
18, Suppl 3
S82-S85
-
51
Schmidt A M, Stern D N.
Hyperinsulinemia and vascular dysfunction: the role of nuclear factor-κB, yet again.
Circ Res.
2000;
87
722-724
-
52
Hofmann M A, Schiekofer S, Kanitz M, Klevesath M S, Joswig M, Lee J, Morcos M, Tritschler H, Ziegler R, Wahl P, Bierhaus A, Nawroth P P.
Insufficient glycemic control increases nuclear factor-κ B binding activity in peripheral blood mononuclear cells isolated from patients with type 1 diabetes.
Diabetes Care.
1998;
21
1310-1316
-
53
Yuan M, Konstantopoulos N, Lee J, Hamnsen L, Li Z W, Karin M, Shoelson S E.
Reversal of obesity - and diet induced insulin resistance with salicylates or targeted disruption of ikkβ.
Science.
2001;
293
1673-1677
-
54
Cooke M S, Evans M D, Dizdarogulu M, Lunec J.
Oxidative DNA damage: mechanisms, mutation and disease.
FASEB.
2003;
17
1195-1214
-
55
Ogihara T, Asano T, Ando K, Chiba Y, Sakoda H, Anai M, Shojima N, Ono H, Onishi Y, Fujishiri M, Katagiri H, Fukuushiam Y, Kikuci M, Noguschi N, Aburatani H, Komuro I, Fujita T.
Angiotensin II-induced insulin resistance is associated with enhanced insulin signaling.
Hypertension.
2002;
40
872-879
-
56
Sharma A M, Janke J, Gorzelniak K, Engeli S, Luft F C.
Angiotensin blockade prevents type 2 diabetes by formation of fat cells.
Hypertension.
2002;
40
609-611
Prof. Dr. Peter Rösen
Abteilung für Klinische Biochemie und Pathobiochemie · Deutsches Diabetes-Forschungsinstitut · Leibniz-Institut an der Heinrich-Heine-Universität
Auf'm Hennekamp 65
40225 Düsseldorf
eMail: roesen@uni-duesseldorf.de
