Many cardiovascular diseases and drug-induced complications are associated with - or even based on - an imbalance between
the formation of reactive oxygen and nitrogen species (RONS) and antioxidant enzymes catalyzing the break-down of these harmful oxidants.
According to the “kindling radical” hypothesis, the formation of RONS may trigger in certain conditions the activation of additional
sources of RONS. According to recent reports, vascular dysfunction in general and cardiovascular complications such as hypertension,
atherosclerosis and coronary artery diseases may be connected to inflammatory processes. The present review is focusing on the uncoupling
of endothelial nitric oxide synthase (eNOS) by different mechanisms involving so-called “redox switches”. The oxidative depletion
of tetrahydrobiopterin (BH4), oxidative disruption of the dimeric eNOS complex, S-glutathionylation and adverse phosphorylation as
well as RONS-triggered increases in levels of asymmetric dimethylarginine (ADMA) will be discussed. But also new concepts of eNOS
uncoupling and state of the art detection of this process will be described. Another part of this review article will address pharmaceutical
interventions preventing or reversing eNOS uncoupling and thereby normalize vascular function in a given disease setting. We finally
turn our attention to the inflammatory mechanisms that are also involved in the development of endothelial dysfunction and cardiovascular
disease. Inflammatory cell and cytokine profiles as well as their interactions, which are among the kindling mechanisms for the development
of vascular dysfunction will be discussed on the basis of the current literature.
Keywords: Oxidative stress, nitric oxide synthase uncoupling, redox switches in nitric oxide synthase, inflammatory cells.
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