© 1999 American Heart Association, Inc.
Editorials |
Regulation of Endothelial NO Synthase mRNA Stability
RNA-Binding Proteins Crowd on the 3'-Untranslated Region
From the Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, Mass.
Correspondence to Kenneth D. Bloch, MD, Cardiovascular Research Center, Massachusetts General Hospital, 149 13th St, Charlestown, MA 02129. E-mail Blochk@helix.mgh.harvard.edu
Key Words: cis-acting sequences • poly(A) tail • endothelial cell
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Introduction |
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Poised at the interface between the bloodstream and underlying vascular smooth muscle, the endothelium produces nitric oxide (NO), a free radical with critical roles in regulating multiple vascular cell functions including vascular tone. In addition, NO modulates the interaction between circulating blood elements and the blood vessel wall. The enzyme responsible for NO production in endothelial cells, endothelial NO synthase (eNOS or NOS3), is also expressed outside the vasculature in cell types such as platelets, cardiac myocytes, neurons, and bronchial epithelial cells. Thus, insights gained from understanding the mechanisms regulating eNOS function in endothelial cells are likely to have important implications beyond vascular biology.
Initially referred to as a "constitutive" NOS, levels of eNOS
in endothelial cells were thought to be static with
enzyme activation achieved via calmodulin binding in
response to increased
[Ca2+]i. However,
following the generation of eNOS-specific antisera and the isolation of
cDNAs encoding eNOS, research from many laboratories has painted a new
picture of the mechanisms controlling eNOS activity with the
identification of multiple additional regulatory steps (reviewed in
Reference 11 ), including posttranslational modification
(phosphorylation, myristoylation, palmitoylation),
intracellular localization (membrane bound versus cytoplasmic,
interaction with caveolae), gene transcription, and mRNA stability. A
wide variety of signals alter eNOS mRNA levels in
endothelial cells including shear stress, oxygen
tension, proliferative status, cytokines, estrogens, growth
factors, oxidized LDL, and 3-hydroxy-3-methylglutaryl-coenzyme A (HMG
CoA) reductase inhibitors. Many of these signals regulate
eNOS mRNA levels, at least in part, by modulating eNOS mRNA stability.
For example, Yoshizumi
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