Transcriptional and posttranscriptional regulation of endothelial nitric oxide synthase expression.
The ability of the endothelium to produce nitric oxide is essential to maintenance of vascular homeostasis; disturbance of this ability is a major contributor to the pathogenesis of vascular disease. In vivo studies have demonstrated that expression of endothelial nitric oxide synthase (eNOS) is vital to endothelial function and have led to the understanding that eNOS expression is subject to modest but significant degrees of regulation. Subsequently, numerous physiological and pathophysiological stimuli have been identified that modulate eNOS expression via mechanisms that alter steady-state eNOS mRNA levels. These mechanisms involve changes in the rate of eNOS gene transcription (transcriptional regulation) and alteration of eNOS mRNA processing and stability (posttranscriptional regulation). In cultured endothelial cells, shear stress, transforming growth factor-beta1, lysophosphatidylcholine, cell growth, oxidized linoleic acid, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, and hydrogen peroxide have been shown to increase eNOS expression. In contrast, tumor necrosis factor-alpha, hypoxia, lipopolysaccaride, thrombin, and oxidized LDL can decrease eNOS mRNA levels. For many of these stimuli, both transcriptional and posttranscriptional mechanisms contribute to regulation of eNOS expression. Recent studies have begun to further define signaling pathways responsible for changes in eNOS expression and have characterized cis- and trans-acting regulatory elements. In addition, a role has been identified for epigenetic control of eNOS mRNA levels. This review will discuss transcriptional and posttranscriptional regulation of eNOS with emphasis on the molecular mechanisms that have been identified for these processes.
Searles
Charles D
CD
Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA. csearle@emory.edu
D020413:3' Untranslated Regions / Q000235:genetics; D000818:Animals; D015971:Gene Expression Regulation, Enzymologic; D006706:Homeostasis / Q000502:physiology; D006801:Humans; D052250:Nitric Oxide Synthase Type III / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics; D014158:Transcription, Genetic
D020413:3' Untranslated Regions; D052250:Nitric Oxide Synthase Type III