Abstract
Background:
NO produced by the endothelial NO synthase (eNOS) is an important regulator of cardiovascular physiological and pathological features. eNOS is activated by numerous stimuli, and its activity is tightly regulated. Platelet-endothelial cell adhesion molecule-1 (PECAM-1) has been implicated in regulating eNOS activity in response to shear stress. The current study was conducted to determine the role of PECAM-1 in the regulation of basal eNOS activity.
Methods and results:
We demonstrate that PECAM-1-knockout ECs have increased basal eNOS activity and NO production. Mechanistically, increased eNOS activity is associated with a decrease in the inhibitory interaction of eNOS with caveolin-1, impaired subcellular localization of eNOS, and decreased eNOS traffic inducer (NOSTRIN) expression in the absence of PECAM-1. Furthermore, we demonstrate that activation of blunted signal transducers and activators of transcription 3 (STAT3) in the absence of PECAM-1 results in decreased NOSTRIN expression via direct binding of the signal transducers and activators of transcription 3 to the NOSTRIN promoter.
Conclusions:
Our results reveal an elegant mechanism of eNOS regulation by PECAM-1 through signal transducers and activators of transcription 3-mediated transcriptional control of NOSTRIN.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing
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Animals
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Binding Sites
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Caveolin 1 / metabolism
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Cells, Cultured
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DNA-Binding Proteins
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Endothelial Cells / drug effects
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Endothelial Cells / enzymology*
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Enzyme Inhibitors / pharmacology
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Humans
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Intracellular Signaling Peptides and Proteins / genetics
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Intracellular Signaling Peptides and Proteins / metabolism*
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Mice
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Mice, Knockout
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Mice, Transgenic
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Nitric Oxide / metabolism*
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Nitric Oxide Synthase Type III / antagonists & inhibitors
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Nitric Oxide Synthase Type III / genetics
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Nitric Oxide Synthase Type III / metabolism*
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Phosphorylation
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Platelet Endothelial Cell Adhesion Molecule-1 / genetics
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Platelet Endothelial Cell Adhesion Molecule-1 / metabolism*
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Promoter Regions, Genetic
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Protein Transport
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RNA Interference
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Recombinant Fusion Proteins / metabolism
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STAT3 Transcription Factor / metabolism*
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Signal Transduction* / drug effects
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Time Factors
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Transcriptional Activation
Substances
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Adaptor Proteins, Signal Transducing
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Cav1 protein, mouse
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Caveolin 1
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DNA-Binding Proteins
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Enzyme Inhibitors
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Intracellular Signaling Peptides and Proteins
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NOSTRIN protein, human
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Platelet Endothelial Cell Adhesion Molecule-1
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Recombinant Fusion Proteins
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STAT3 Transcription Factor
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STAT3 protein, human
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Stat3 protein, mouse
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Nitric Oxide
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NOS3 protein, human
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Nitric Oxide Synthase Type III
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Nos3 protein, mouse