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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.

Original publication

DOI

10.1161/ATVBAHA.110.216200

Type

Journal article

Journal

Arterioscler Thromb Vasc Biol

Publication Date

03/2011

Volume

31

Pages

643 - 649

Keywords

Animals, Binding Sites, Caveolin 1, Cells, Cultured, Endothelial Cells, Enzyme Inhibitors, Humans, Intracellular Signaling Peptides and Proteins, Mice, Mice, Knockout, Mice, Transgenic, Nitric Oxide, Nitric Oxide Synthase Type III, Phosphorylation, Platelet Endothelial Cell Adhesion Molecule-1, Promoter Regions, Genetic, Protein Transport, RNA Interference, Recombinant Fusion Proteins, STAT3 Transcription Factor, Signal Transduction, Time Factors, Transcriptional Activation