Abstract
The Global Burden of Disease Study identified cardiovascular risk factors as leading causes of global deaths and life years lost. Endothelial dysfunction represents a pathomechanism that is associated with most of these risk factors and stressors, and represents an early (subclinical) marker/predictor of atherosclerosis. Oxidative stress is a trigger of endothelial dysfunction and it is a hall-mark of cardiovascular diseases and of the risk factors/stressors that are responsible for their initiation. Endothelial function is largely based on endothelial nitric oxide synthase (eNOS) function and activity. Likewise, oxidative stress can lead to the loss of eNOS activity or even “uncoupling” of the enzyme by adverse regulation of well-defined “redox switches” in eNOS itself or up-/down-stream signaling molecules. Of note, not only eNOS function and activity in the endothelium are essential for vascular integrity and homeostasis, but also eNOS in perivascular adipose tissue plays an important role for these processes. Accordingly, eNOS protein represents an attractive therapeutic target that, so far, was not pharmacologically exploited. With our present work, we want to provide an overview on recent advances and future therapeutic strategies that could be used to target eNOS activity and function in cardiovascular (and other) diseases, including life style changes and epigenetic modulations. We highlight the redox-regulatory mechanisms in eNOS function and up- and down-stream signaling pathways (e.g., tetrahydrobiopterin metabolism and soluble guanylyl cyclase/cGMP pathway) and their potential pharmacological exploitation.
Highlights
Cardiovascular diseases/events represent significant health risk factors and they are major contributors to global deaths and chronic illness/disability [1]
Based on the data of the Global Burden of Disease Study, there was a significant shift regarding the impact of different risk factors on the global disease burden and life expectancy during the last 20 years, away from communicable childhood diseases towards those for non-communicable diseases that are found in the aging population [2,3]
The functional correlate of endothelial nitric oxide synthase (eNOS) dysfunction/uncoupling is endothelial dysfunction in coronary and peripheral vessels, which can be measured by acetylcholine-dependent or flow-mediated dilation (FMD) and it represents an early predictor of cardiovascular events via its direct connection to the process of atherosclerosis [26,27]
Summary
Cardiovascular diseases/events (e.g., heart failure, myocardial infarction, acute coronary syndromes) represent significant health risk factors and they are major contributors to global deaths and chronic illness/disability [1]. According to the concept of “kindling radicals” or “bonfire” hypothesis, the initial formation of superoxide (e.g., from phagocytic nicotinamide adenine dinucleotide phosphate (NADPH) oxidases, professional enzymes for synthesis of superoxide, of infiltrated leukocytes) and the subsequent formation of peroxynitrite represent the mechanism of eNOS uncoupling [23] This kind of ROS-induced ROS formation is well known for cross-activation of mitochondrial ROS formation by dysfunctional. Despite the preclinical and clinical evidence for an important role of oxidative stress for the development and progression of cardiovascular disease, there are, to date, only a few examples of clinical studies demonstrating that targeted antioxidant drugs (e.g., xanthine oxidase inhibitors, meta-analysis in 10,684 individuals) or tight control of vitamin C plasma levels (e.g., EPIC-Norfolk trial, 19,496 individuals [39]) improve the prognosis of patients with cardiovascular disease. The majority of large clinical trials failed to show any health benefit for the treatment of cardiovascular disease with non-selective antioxidant drugs [40,41], and the synthetic antioxidant drug NXY-059, despite costly development/clinical testing, failed to demonstrate any benefit in 3195 stroke patients [42]
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