Understanding eNOS for Pharmacological Modulation of Endothelial Function: A Translational View

Abstract

Knowledge about the function of endothelial nitric oxide synthase (eNOS), and its regulation in pathophysiological states has tremendously increased. It is now clear that diminished activity of nitric oxide (NO) contributes to endothelial dysfunction, which is a characteristic of impeding atherosclerosis. This review aims to summarize the available knowledge about the impact of important cardiovascular risk factors on NO production by eNOS. There are 4 principle causes of diminished NO bio-activity: decreased expression and/or activity of the eNOS enzyme, eNOS uncoupling, enhanced breakdown or scavenging of NO and impaired transmission of NO-mediated signaling events (failure of the effector mechanisms). From the analysis, it becomes clear, that several aspects of eNOS functionality have only scarcely been tested under conditions of increased (experimental) cardiovascular risk. These aspects include palmitoylation, myristoylation and phosphorylation of the eNOS enzyme. Clear is that enhanced production of reactive oxygen species (ROS) and eNOS uncoupling are relatively important causes of reduced NO-bioactivity in cardiovascular disease states. Ideally, eNOS is sufficiently expressed, produces NO sufficiently and not abundantly, does not produce superoxide and is not scavenged by ROS; the produced NO then reaches its signaling target, mainly soluble guanylyl cyclase (sGC) and elicits a cellular response. Considering which aspects of eNOS are now assessable in a clinical setting and which therapeutic measures are available, there is a great challenge ahead.

Nitric Oxide Production and Endothelium-Dependent Vasorelaxation Ameliorated by N 1 -Methylnicotinamide in Human Blood Vessels

“…[7][8][9][10] It is, therefore, important to seek out effective strategies aimed at preventing or treating endothelial dysfunction via increasing the bioavailability of NO derived from eNOS. Our study reports for the first time that MNA ϩ , a primary metabolite of NA, is potent in increasing eNOS-mediated NO release from the endothelial cells.…”

“…7,[9][10][11] This consequently leads to an O 2 ·Ϫ reaction with NO, resulting in the formation of highly reactive and cytotoxic peroxynitrite and the loss of NO bioavailability. …”

“…[7][8][9][10] Although NO bioavailability is decreased in dysfunctional endothelium, the levels of eNOS mRNA and protein are maintained or even enhanced but associated with the increased NO synthasedependent superoxide (O 2 ·Ϫ ) formation because of the enzymatic "uncoupling" of NO synthase; electron flow through the eNOS enzyme is then diverted to molecular oxygen rather than to l-arginine, which facilitates the production of O 2 ·Ϫ rather than NO. 7,[9][10][11] This consequently leads to an O 2 ·Ϫ reaction with NO, resulting in the formation of highly reactive and cytotoxic peroxynitrite and the loss of NO bioavailability.…”

Protein myristoylation in health and disease

“…These proteins have a broad range of functions and include protein kinases and phosphatases, G α proteins, nitric oxide synthase [88], ADPribosylation factors (ARFs), calcium binding proteins and membrane or cytoskeleton-associated structural proteins such as MARCKS [21,61]. Many of these proteins are involved in signalling cascades.…”

Expression of eNOS in kidneys from hypertensive patients

“…The released NO diffuses to the underlying vascular smooth muscle cells and activates soluble guanylate cyclase, leading to an increase in cGMP resulting in relaxation. 18,19 Together with vasoconstrictive mediators, renal endothelial cell-derived NO plays a critical role in regulation of renal blood flow and eNOs in kidneys from hypertensive patients Dovepress submit your manuscript | www.dovepress.com Dovepress glomerular filtration rate. Endothelial NOS produced NO is also responsible for modulation of angiotensin II-mediated renal norepinephrine release.…”