Susanne Karbach, Philip Wenzel, Ari Waisman, Thomas Munzel and Andreas Daiber Pages 3579 - 3594 ( 16 )
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.
Oxidative stress, nitric oxide synthase uncoupling, redox switches in nitric oxide synthase, inflammatory cells.
Universitatsmedizin der Johannes Gutenberg-Universitat Mainz, II. MedizinischeKlinik und Poliklinik – Labor für Molekulare Kadiologie, Geb. 605 – Raum 3.262, Langenbeckstr. 1, 55131 Mainz, Germany.