Platelet-endothelial cell adhesion molecule-1 regulates endothelial NO synthase activity and localization through signal transducers and activators of transcription 3-dependent NOSTRIN expression. Arterioscler Thromb Vasc Biol 2011 Mar;31(3):643-9
Date
12/25/2010Pubmed ID
21183735Pubmed Central ID
PMC3041848DOI
10.1161/ATVBAHA.110.216200Scopus ID
2-s2.0-79952188007 (requires institutional sign-in at Scopus site) 35 CitationsAbstract
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.
Author List
McCormick ME, Goel R, Fulton D, Oess S, Newman D, Tzima EAuthors
Debra K. Newman PhD Investigator in the Blood Research Institute department at BloodCenter of WisconsinDebra K. Newman PhD Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
Adaptor Proteins, Signal TransducingAnimals
Binding Sites
Caveolin 1
Cells, Cultured
DNA-Binding Proteins
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