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

Author(s): Branko Braam and Marianne C. Verhaar

Affiliation: Div. Nephrology of the Dept.of Medicine and Dept. Physiology, CSB 11-107, University of Alberta, Edmonton, AB T6G 2B7, Canada.

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 NOmediated 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.

Keywords: Nitric oxide, eNOS uncoupling, chronic renal failure, diabetes mellitus, hypercholesterolemia, atherosclerosis

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Article Details

VOLUME: 13
ISSUE: 17
Page: [1727 - 1740]
Pages: 14
DOI: 10.2174/138161207780831275
Price: $58