Regulation of Endothelial NO Synthase mRNA Stability
RNA-Binding Proteins Crowd on the 3′-Untranslated Region
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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 et al2 observed that incubation of human umbilical vein endothelial cells with tumor necrosis factor-α (TNF-α) decreased eNOS mRNA by decreasing the stability of the mRNA >10-fold. In addition, Laufs et al3 reported HMG CoA reductase inhibitors attenuated the ability of hypoxia to destabilize eNOS …