Protein kinase Cδ regulates endothelial nitric oxide synthase expression via Akt activation and nitric oxide generation

Sud, Neetu; Wedgwood, Stephen; Black, Stephen M.

doi:10.1152/ajplung.00353.2007

Cited by 14 publications

(22 citation statements)

References 56 publications

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“…Ca 2ϩ -independent isoforms, notably PKC, may also be important in IEJ disruption, which predominantly seems to require RhoA-induced signaling (91). PKC␦ was shown to regulate focal adhesions and RhoA activity (57) as well as to induce NO generation via stimulating Akt activity (133). While some studies showed that PKC␦ maintains basal barrier function, another showed that inhibition of PKC␦ prevented phorbol ester-mediated barrier dysfunction (57).…”

Section: Endothelial Scaffoldsmentioning

confidence: 99%

Novel regulators of endothelial barrier function

Mehta

Ravindran

Kuebler

2014

American Journal of Physiology-Lung Cellular and Molecular Phys

109

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Endothelial barrier function is an essential and tightly regulated process that ensures proper compartmentalization of the vascular and interstitial space, while allowing for the diffusive exchange of small molecules and the controlled trafficking of macromolecules and immune cells. Failure to control endothelial barrier integrity results in excessive leakage of fluid and proteins from the vasculature that can rapidly become fatal in scenarios such as sepsis or the acute respiratory distress syndrome. Here, we highlight recent advances in our understanding on the regulation of endothelial permeability, with a specific focus on the endothelial glycocalyx and endothelial scaffolds, regulatory intracellular signaling cascades, as well as triggers and mediators that either disrupt or enhance endothelial barrier integrity, and provide our perspective as to areas of seeming controversy and knowledge gaps, respectively.

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Section: Endothelial Scaffoldsmentioning

confidence: 99%

Novel regulators of endothelial barrier function

Mehta

Ravindran

Kuebler

2014

American Journal of Physiology-Lung Cellular and Molecular Phys

109

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“…However, it has also been suggested that the PKC isoforms ␣, ␦, and ⑀ are upstream of Akt activation and eNOS phosphorylation on Ser 1177 . [10][11][12] Together, these posttranslational modifications contribute significantly to the positive and negative regulation of eNOS activity and consequently to NO release from endothelial cells after exposure to VEGF.…”

Section: Introductionmentioning

confidence: 99%

Phosphorylation of endothelial nitric oxide synthase by atypical PKCζ contributes to angiopoietin-1–dependent inhibition of VEGF-induced endothelial permeability in vitro

Oubaha

Gratton

2009

Blood

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Vascular endothelial growth factor (VEGF) is a potent angiogenic cytokine that also increases vascular permeability. Nitric oxide (NO) released from endothelial cells, after activation of endothelial NO synthase (eNOS), contributes to proangiogenic and permeability effects of VEGF. Angiopoietin-1 (Ang-1), via Tie2 receptors, shares many of the proangiogenic properties of VEGF on endothelial cells. However, in contrast to VEGF, Ang-1 protects blood vessels from increased plasma leakage, which contributes to their stabilization. Because eNOS-derived NO is central to increased permeability in response to VEGF, we investigated whether Ang-1 interferes with VEGF signaling to eNOS. We demonstrate that Ang-1 stimulation of endothelial cells inhibits VEGF-induced NO release and transendothelial permeability. In contrast to VEGF stimulation, Ang-1 causes a marked protein kinase C (PKC)–dependent increase in phosphorylation of eNOS on the inhibitory Thr497. Furthermore, using pharmacologic inhibitors, overexpression studies, and small interfering RNA-mediated gene silencing, we demonstrate that atypical PKCζ is responsible for phosphorylation of eNOS on Thr497 in response to Ang-1. In addition, PKCζ knockdown abrogates the capacity of Ang-1 to inhibit VEGF-induced NO release and endothelial permeability. Thus, inhibition of NO production by Ang-1, via phosphorylation of eNOS on Thr497 by PKCζ, is responsible, at least in part, for inhibition of VEGF-stimulated endothelial permeability by Ang-1.

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“…Indeed it is possible that there may be some iosforms that activate, while others inhibit, NO signaling. We (40) have recently shown that PKC␦ is involved in maintaining basal eNOS expression through its ability to activate Akt and increase NO generation. In support of this premise, studies have shown that, depending on the tissue analyzed, PKC can either positively (25,50) or negatively (29,57) regulate eNOS expression and activity.…”

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confidence: 99%

Modulation of PKCδ signaling alters the shear stress-mediated increases in endothelial nitric oxide synthase transcription: role of STAT3

Sud

Kumar

Wedgwood³

et al. 2009

American Journal of Physiology-Lung Cellular and Molecular Phys

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We have previously shown that the regulation of endothelial nitric oxide synthase (eNOS) in endothelial cells isolated from fetal lamb under static conditions is positively regulated by PKCdelta. In this study, we explore the role of PKCdelta in regulating shear-induced upregulation of eNOS. We found that shear caused a decrease in PKCdelta activation. Modulation of PKCdelta before shear with a dominant negative mutant of PKCdelta (DN PKCdelta) or bryostatin (a known PKCdelta activator) demonstrated that PKCdelta inhibition potentiates the shear-mediated increases in eNOS expression and activity, while PKCdelta activation inhibited these events. To gain insight into the mechanism by which PKCdelta inhibits shear-induced eNOS expression, we examined activation of STAT3, a known target for PKCdelta phosphorylation. We found that shear decreased the phosphorylation of STAT3. Further the transfection of cells with DN PKCdelta reduced, while PKCdelta activation enhanced, STAT3 phosphorylation in the presence of shear. Transfection of cells with a dominant negative mutant of STAT3 enhanced eNOS promoter activity and nitric oxide production in response to shear. Finally, we found that mutating the STAT3 binding site sequence within the eNOS promoter increased promoter activity in response to shear and that this was no longer inhibited by bryostatin. In conclusion, shear decreases PKCdelta activity and, subsequently, reduces STAT3 binding to the eNOS promoter. This signaling pathway plays a previously unidentified role in the regulation of eNOS expression by shear stress.

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Protein kinase Cδ regulates endothelial nitric oxide synthase expression via Akt activation and nitric oxide generation

Cited by 14 publications

References 56 publications

Novel regulators of endothelial barrier function

Novel regulators of endothelial barrier function

Phosphorylation of endothelial nitric oxide synthase by atypical PKCζ contributes to angiopoietin-1–dependent inhibition of VEGF-induced endothelial permeability in vitro

Modulation of PKCδ signaling alters the shear stress-mediated increases in endothelial nitric oxide synthase transcription: role of STAT3

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