Reaktive Sauerstoffspezies als Ursache der endothelialen Dysfunktion im Diabetes

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

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