Oxidative stress and vascular function

Andreas Daiber, Michael Mader, Paul Stamm, Elena Zinßius, Swenja Kröller-Schön, Matthias Oelze, Thomas Münzel
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Abstract


Many drug-induced complications and diseases are known to be associated with or even based on a dysequilibrium between the formation of reactive oxygen or nitrogen species (RONS) and the expression/activity of antioxidant enzymes that catalyze the breakdown of these harmful reactive species. The “kindling radical” concept is based on the initial formation of RONS that in turn activate additional sources of RONS in certain pathological conditions. Recently, we and others have demonstrated such “cross-talk” between NADPH oxidases and mitochondria in the setting of nitroglycerin-induced nitrate tolerance, the aging process and angiotensin-II triggered arterial hypertension via redox pathways compromising the mitochondrial, ATP-sensitive potassium channel (mKATP), the mitochondrial permeability transition pore (mPTP), cSrc and protein kinases and the NADPH oxidase isoform Nox2 (and eventually Nox1). This review will focus on the uncoupling of endothelial nitric oxide synthase (eNOS) by initially formed “kindling radicals” (RONS) and on the different “redox switches” that are involved in the uncoupling process of eNOS. S-glutathionylation of the eNOS reductase domain, adverse phosphorylation of eNOS, and of course the oxidative depletion of tetrahydrobiopterin (BH4) will be highlighted as potential “redox switches” in eNOS. In addition, RONS-triggered increases in levels of asymmetric dimethylarginine (ADMA) and L-arginine depletion will be discussed as alternative reasons for dysfunctional eNOS. Finally, we present the clinical perspectives of eNOS uncoupling (and dysfunction) for the development and progression of cardiovascular disease and discuss the important prognostic value of the measurement of endothelial function (e.g. by flow-mediated dilation or forearm plethysmography) for patients with cardiovascular disease.

Keywords


Ion channels, cell biochemistry, biophysics, calcium signaling, cellular function, cellular physiology, metabolism, apoptosis, lipid peroxidation, nitric oxide synthase, ageing, antioxidants, neuropathy

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References


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