eNOS Uncoupling in Cardiovascular Diseases - the Role of Oxidative Stress and Inflammation

Abstract

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.

Emerging Roles of the Mineralocorticoid Receptor in Pathology: Toward New Paradigms in Clinical Pharmacology

“…Oxidative stress increases DNA damage (Schupp et al, 2010) and protein carbonylation (Di Zhang et al, 2008). Uncoupling of the NO synthase decreases the availability of NO for vasorelaxation, as well as increased production of hydrogen peroxide, and activation of the nuclear factor kB pathway leading to inflammation and fibrosis (Mayyas et al, 2013;Karbach et al, 2014) …”

High Homocysteine Levels are Closely Associated with the Categories of Coronary Artery Diseases as well as Low Status of Folic Acid and Vitamin B12

“…NO as a most important mediator of endothelium-dependent relaxation, plays a key role in normal vascular physiology in preserving the vessel wall in a quiescent state by inhibition of inflammation, thrombosis, and cellular proliferation. This gas is a potent vasodilator to activate soluble guanylyl cyclase in vascular muscle, resulting in accumulation of cGMP and relaxation, which is produced from Larginine by the action of endothelial NO synthase (eNOS) in the presence of several cofactors [18].…”

Taking up the cudgels for the traditional reactive oxygen and nitrogen species detection assays and their use in the cardiovascular system

“…In the long run, this will lead to accumulation of oxidative damage in biomolecules and impaired cellular redox regulation, a condition that is termed oxidative stress [3,4]. Many cardiovascular, neurodegenerative, and inflammatory diseases as well as cancer have been demonstrated to be associated with or even triggered by oxidative stress [5][6][7][8]. The latter is a well-established hallmark of cardiovascular disease [9] as supported by phenotypic changes in animal models upon genetic manipulation of enzymes involved in the synthesis or detoxification of ROS and RNS [1,10,11].…”