New Therapeutic Implications of Endothelial Nitric Oxide Synthase (eNOS) Function/Dysfunction in Cardiovascular Disease

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.

Triglyceride/High-Density Lipoprotein Cholesterol Ratio Is Associated with In-Hospital Mortality in Acute Type B Aortic Dissection

“…Recent evidence suggests that inflammatory factors and oxidative stress play a crucial role in the pathogenesis and progression of AAD [32,33]. For instance, Daiber et al [34] reported the quality of high-density lipoprotein changes under oxidative stress conditions. Similarly, Kaye et al [35] found that if the levels of HDL are insufficient, cholesterol and lipids in arterial walls trigger an exacerbated inflammatory response.…”

Role of Asymmetric Dimethylarginine and Nitric Oxide in Type 2 Diabetes Mellitus and Its Cardiovascular Complications

“…Also, Taner et al (2013) indicated that serum ADMA may play a role in both the pathophysiology and screening of masked hypertension in diabetic subjects. Accordingly, future therapeutic strategies that could be used to target NOS (Daiber et al, 2019) and/or DDAH (Jarzebska et al, 2019) activity could be promising in the management of cardiovascular and other vascular complications of diabetes mellitus.…”

Arginine Derivatives in Cerebrovascular Diseases: Mechanisms and Clinical Implications

“…During the acute stages of stroke, ADMA levels are increased by oxidative stress resulting in activation of PRMTs and inhibition of DDAH activity [126,127]. Here, ADMA might be a further generator of oxidative stress via uncoupling of eNOS and iNOS, which leads to synthesis of superoxides [126,128,129]. So far, studies are missing that show ADMA induced uncoupling of NOS in the cerebral circulation.…”