Regulation of Endothelial Nitric Oxide Synthase Activity and Gene Expression

  title={Regulation of Endothelial Nitric Oxide Synthase Activity and Gene Expression},
  author={Kenneth K. Wu},
  journal={Annals of the New York Academy of Sciences},
  • K. Wu
  • Published 1 May 2002
  • Biology
  • Annals of the New York Academy of Sciences
Abstract: Endothelial nitric oxide synthase (eNOS) is constitutively expressed in endothelial cells lining the blood vessel and the heart. It plays a major role in vascular and tissue protection. Its activity is tightly controlled by an intramolecular autoinhibitory element that hinders calmodulin binding. This molecular hindrance is removed by elevated intracellular calcium levels. The catalytic activity of eNOS is augmented by phosphorylation of a C‐terminal serine residue (Ser‐1177 of human… 

Downregulation of human endothelial nitric oxide synthase promoter activity by p38 mitogen-activated protein kinase activation.

The findings strongly suggest that the activation of the p38 MAPK signaling pathway may be implicated in the downregulation of human eNOS promoter activity.

Transcriptional and posttranscriptional regulation of endothelial nitric oxide synthase expression.

  • C. Searles
  • Biology
    American journal of physiology. Cell physiology
  • 2006
The ability of the endothelium to produce nitric oxide is essential to maintenance of vascular homeostasis; disturbance of this ability is a major contributor to the pathogenesis of vascular disease.

Lysophosphatidylcholine up-regulates human endothelial nitric oxide synthase gene transactivity by c-Jun N-terminal kinase signalling pathway

It was observed by electrophoretic mobility shift assay that LPC stimulated both SP1 and AP1 DNA binding activity to go up, and using decoy oligonucleotides proved that SP1 was necessary for maintaining the basal or stimulated trans activity, whereas AP1 contributed mainly to the increase of the stimulated transactivity.

Serine 1179 Phosphorylation of Endothelial Nitric Oxide Synthase Increases Superoxide Generation and Alters Cofactor Regulation

It is demonstrated that eNOS serine 1179 phosphorylation, in addition to enhancing NO production, also profoundly affects superoxide generation: S1179osphorylation increases superoxide production while decreasing sensitivity to the inhibitory effect of BH4 on this activity.

Betulinic Acid Increases eNOS Phosphorylation and NO Synthesis via the Calcium-Signaling Pathway.

Results indicate that BA activates eNOS phosphorylation and NO synthesis via the Ca(2+)/CaMKII and Ca( 2+)/ CaMKK/AMPK pathways, which provide further insight into the eN OS signaling pathways involved in the antiatherosclerosis effects of BA.

Progesterone promotes endothelial nitric oxide synthase expression through enhancing nuclear progesterone receptor-SP1 formation.

Progesterone modulates eNOS expression through promoting PR-A-SP1 complex formation and progesterone antagonist attenuates eNos expression leading to the loss of vascular relaxation.

Long‐term up‐regulation of eNOS and improvement of endothelial function by inhibition of the ubiquitin–proteasome pathway

  • V. StanglM. Lorenz K. Stangl
  • Biology, Chemistry
    FASEB journal : official publication of the Federation of American Societies for Experimental Biology
  • 2004
Results indicate that low‐dose proteasome inhibition enhances eNOS expression and activity, and improves endothelial function, as evidenced by accumulation of poly‐ubiquitinylated proteins and by measuring proteasomal activity in cell extracts.

16K-prolactin inhibits activation of endothelial nitric oxide synthase, intracellular calcium mobilization, and endothelium-dependent vasorelaxation.

16K-PRL can block the Ca(2+)-mediated activation of eNOS by three different vasoactive substances, and this action results in the inhibition of both angiogenesis and vasorelaxation.



Activation of nitric oxide synthase in endothelial cells by Akt-dependent phosphorylation

It is demonstrated that the serine/threonine protein kinase Akt/PKB mediates the activation of eNOS, leading to increased NO production, and represents a novel Ca2+-independent regulatory mechanism for activation ofeNOS.

Regulation of endothelium-derived nitric oxide production by the protein kinase Akt

It is shown that the serine/threonine protein kinase Akt (protein kinase B) can directly phosphorylate eNOS on serine 1179 and activate the enzyme, leading to NO production, whereas mutant eN OS (S1179A) is resistant to phosphorylation and activation by Akt.

Endothelial Nitric Oxide Synthase: A New Paradigm for Gene Regulation in the Injured Blood Vessel

In models of inflammation, proliferation/injury, oxidized low-density lipoprotein treatment, and hypoxia, eNOS mRNA destabilization plays a significant role in the rapid downregulation of eNos mRNA levels.

Dynamic activation of endothelial nitric oxide synthase by Hsp90

Inhibition of signalling through Hsp90 attenuates both agonist-stimulated production of nitric oxide and endothelium-dependent relaxation of isolated blood vessels and indicates that in addition to its role as a molecular chaperone involved in protein folding and maturation, HSp90 may also be recruited to cellular targets depending on the activation state of the cell.

Transcriptional Regulation of Endothelial Nitric-oxide Synthase by an Interaction between Casein Kinase 2 and Protein Phosphatase 2A*

Results indicate that Sp1 binding to its cognate site on the endothelial nitric-oxide synthase promoter and its transactivation of endothelial Nitric- oxide synthase is regulated by post-translational Sp1 phosphorylation and dephosphorylation through a dynamic interaction between casein kinase 2 and protein serine/threonine phosphatase 2A.

Reconstitution of an Endothelial Nitric-oxide Synthase (eNOS), hsp90, and Caveolin-1 Complex in Vitro

Results show that the actions of CaM on eNOS dissociation from caveolin are facilitated in the presence of hsp90, and eNos enzymatic activity is also less sensitive to inhibition by the caveolin scaffolding peptide when eN OS is prebound to hSp90.

Reciprocal Regulation of Endothelial Nitric-oxide Synthase by Ca2+-Calmodulin and Caveolin*

It is reported that in endothelial cells the interaction between eNOS and caveolin is importantly regulated by Ca2-calmodulin, and this findings may have broad implications for the regulation of Ca2+-dependent signal transduction in plasmalemmal caveolae.

Role of Sp1 in transcriptional activation of human nitric oxide synthase type III gene.

Findings provide strong evidence that binding of Sp1 or closely related protein to this site is required for the activation of basal NOS-III transcription.

Structure and chromosomal localization of the human constitutive endothelial nitric oxide synthase gene.

Characterization of 5'-flanking genomic regions indicates that the endothelial NO synthase promoter is "TATA-less" and exhibits proximal promoter elements consistent with a constitutively expressed gene that is found in endothelial cells, namely Sp1 and GATA motifs.

Transcriptional Induction of Endothelial Nitric Oxide Synthase Type III by Lysophosphatidylcholine (*)

In human umbilical vein endothelial cells lysophosphatidylcholine (lyso-PC), a component of atherogenic lipoproteins and atherosclerotic lesions, increases NOS-III mRNA and protein levels, which leads to the augmentation of Nos-III activity and the enhancement of anti-platelet properties of endothelial Cells.