1. Platelet-endothelial cell adhesion molecule-1 regulates endothelial NO synthase activity and localization through signal transducers and activators of transcription 3-dependent NOSTRIN expression.
- Author
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McCormick ME, Goel R, Fulton D, Oess S, Newman D, and Tzima E
- Subjects
- Adaptor Proteins, Signal Transducing, Animals, Binding Sites, Caveolin 1 metabolism, Cells, Cultured, DNA-Binding Proteins, Endothelial Cells drug effects, Enzyme Inhibitors pharmacology, Humans, Intracellular Signaling Peptides and Proteins genetics, Mice, Mice, Knockout, Mice, Transgenic, Nitric Oxide Synthase Type III antagonists & inhibitors, Nitric Oxide Synthase Type III genetics, Phosphorylation, Platelet Endothelial Cell Adhesion Molecule-1 genetics, Promoter Regions, Genetic, Protein Transport, RNA Interference, Recombinant Fusion Proteins metabolism, Time Factors, Transcriptional Activation, Endothelial Cells enzymology, Intracellular Signaling Peptides and Proteins metabolism, Nitric Oxide metabolism, Nitric Oxide Synthase Type III metabolism, Platelet Endothelial Cell Adhesion Molecule-1 metabolism, STAT3 Transcription Factor metabolism, Signal Transduction drug effects
- 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.
- Published
- 2011
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