Regulation of Endothelial Nitric Oxide Synthase by Protein Kinase C

Matsubara, Mamoru; Hayashi, Nobuhiro; Jing, Tao; Titani, Koiti

doi:10.1093/jb/mvg099

Cited by 103 publications

(63 citation statements)

References 52 publications

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“…This result is similar to those obtained with vertebrate cells, where PKC is known to induce the inhibition of nitric oxide synthases (NOS) (31,32).…”

Section: Discussionsupporting

confidence: 87%

Implication of PKC in the seasonal variation of the immune response of the hemocytes of Mytilus galloprovincialis Lmk. and its role in interleukin‐2‐induced nitric oxide synthesis

2007

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SummaryThe hemocytes are the cells responsible for the immune response in marine mollusks. The role of NO in processes related to the activation of the hemocytes has turned out evident over the late years. In the case of the mussel Mytilus galloprovincialis Lmk., hemocyte NO basal production varies throughout the year, showing a maximum in summer and a minimum in winter. IL-2 reverts the low winter NO basal production through a process mediated by cAMP-dependent protein kinase and by an apparent side effect of protein kinase C. The seasonal variation of NO production in the presence of the PKC inhibitor bisindolylmaleimide (BSM) allows suggesting a model in which PKC would modulate the activity of the enzymes responsible for nitric oxide production.

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“…This result is similar to those obtained with vertebrate cells, where PKC is known to induce the inhibition of nitric oxide synthases (NOS) (31,32).…”

Section: Discussionsupporting

confidence: 87%

Implication of PKC in the seasonal variation of the immune response of the hemocytes of Mytilus galloprovincialis Lmk. and its role in interleukin‐2‐induced nitric oxide synthesis

2007

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“…In support of this possibility are the combined observations that phorbol ester (protein kinase C activator) (1) reversed shear stressincreased NO release (as determined by lowered cyclic GMP levels) although to a lessor magnitude than L-NNA (reported as data not shown by Kuchan and Frangos 35 ). Indeed, phorbol ester-lowered NO release is consistent protein kinase C negative regulation of NOS activity, 63 (2) did not reverse the lowered ET-1 levels, but (3) in the presence of NOS inhibitor, reversed shear stress-lowered ET-1 release. 35 Therefore, combined phorbol ester and NOS inhibitor may have lowered NO release to a level where ET-1 release could then be regulated ( Figure S1).…”

Section: Resultsmentioning

confidence: 92%

Nitric Oxide Inhibition of Endothelin-1 Release in the Vasculature

Rapoport

2014

Hypertension

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A key function of endothelial derived nitric oxide (NO) is to limit the constrictor capacity of endothelin (ET)-1.1,2 Thus, an imbalance between NO and ET-1 can result in ET-1-dependent increased vascular tone.1 Indeed, the importance of sustained, NO inhibition of the ET-1 drive to increase tone is exemplified in vivo by the rapid, ET-1-mediated arterial pressure elevation after acute NO synthase (NOS) inhibition. Moreover, the ET-1 pressor effect after NOS inhibition is independent of other pressor systems and, thus, reflects the relative importance of NO suppression of this ET-1 drive.2 Two, nonmutually exclusive mechanisms thought to underlie the ET-1 dependency of the increased vascular tone responsible for the NOS inhibitor-induced pressure elevation are (1) NO inhibition of constriction to endogenously released ET-1.1,2 This mechanism is essentially supported by demonstrations that NOS inhibitor enhanced the constrictor effects of exogenous ET-1 in several in vivo and ex vivo preparations. 3-14Thus, an assumption underlying these observations is that the constrictor actions of exogenous and endogenous ET-1 are similarly affected by NO; (2) NO inhibition of ET-1 release. 1,2Although the detailed mechanism underlying the NO inhibition of acute ET-1 release has not been clearly established, possibilities include decreased conversion of the immediate precursor to ET-1, big ET-1, to ET-1 15 and inhibition of pathways involved in the exocytosis of Weibel-Palade bodies, 16 endothelial granules that store ET-1. 17 However, it should be noted that in vivo findings that actually demonstrate the fundamental phenomenon of NO inhibition of ET-1 release are generally lacking.2 Thus, studies purported to demonstrate NO inhibition of ET-1 release have relied largely on isolated vessels and cultured endothelium, as described herein.This review assessed these in vitro findings, with a specific focus toward elucidating the mechanism underlying the NO-mediated negative regulation of ET-1-dependent increased arterial pressure, as demonstrated after acute NOS inhibitor in vivo.2 Findings referred to are mainly those of ET-1 release rather than contractility (eg, those in which ET receptor antagonist prevented the NOS inhibitor-induced decreased flow/increased pressure/tension). 12,18-25 The rationale for this emphasis is that findings based on contractility could reflect NOS inhibitor enhancement of ET-1 constriction rather than increased ET-1 release. Furthermore, we also focus on whether laminar shear stress influences the manifestation of NO inhibition of ET-1 release. That is, the endothelium of arteries that are anatomically linear is subjected to high levels of shear stress while, for example, at bifurcated arterial locations is subjected to low levels of shear stress, regions associated with atherosclerosis. 26 Acute NOS Inhibition/No Donors and ET-1 Release ArteriesIn rat heart perfused at constant flow, increased amounts of ET-1 were detected in the coronary effluent of samples collected for the final 5 to 15 minutes ...

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“…8 -11 Conversely, the phosphorylation of eNOS-Thr497 decreases eNOS activity, 8,10 which is mediated by AMP-activated protein kinase 5 and protein kinase C (PKC). 10,12 This site is also dephosphorylated by phosphatases, such as protein phosphatase 1 and protein phosphatase 2B, which results in an increase in NO production. 3,10 Two other sites, eNOSSer635 and eNOS-Ser617, have also been identified as phosphorylation targets of PKA and Akt, respectively.…”

mentioning

confidence: 99%

Cyclin-Dependent Kinase 5 Phosphorylates Endothelial Nitric Oxide Synthase at Serine 116

Cho

Seo²,

Park³

et al. 2010

Hypertension

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Abstract-Nitric oxide (NO) production in endothelial cells (EC) is regulated by multisite phosphorylation of specific serine and threonine residues in endothelial NO synthase (eNOS). Among these, eNOS-Ser116 is phosphorylated in the basal state, and its phosphorylation contributes to basal NO production. Here, we investigated the mechanism by which eNOS-Ser116 is phosphorylated during the basal state using bovine aortic EC. Although a previous study suggested that protein kinase C was involved in eNOS-Ser116 phosphorylation, overexpression of various protein kinase C isoforms did not affect eNOS-Ser116 phosphorylation. An in silico analysis using a motif scan revealed that the eNOS-Ser116 residue might be a substrate for proline-directed protein kinases. Roscovitine, a specific inhibitor of cyclin-dependent kinase (CDK), 1, 2, and 5, but not an inhibitor of mitogen-activated protein kinase kinase or glycogen synthase kinase 3␤, inhibited eNOS-Ser116 phosphorylation dose dependently. Furthermore, purified CDK1, 2, or 5 directly phosphorylated eNOS-Ser116 in vitro. Ectopic expression of the dominant-negative CDK5 but not dominant-negative CDK1 or dominant-negative CDK2 repressed eNOS-Ser116 phosphorylation and increased NO production. In addition, CDK5 activity was detected in bovine aortic EC, and coimmunoprecipitation and confocal microscopy studies revealed a colocalization of eNOS and CDK5. Cotransfection of CDK5 and p25, the specific CDK5 activator, increased eNOS-Ser116 phosphorylation and decreased NO production, but its parent molecule, p35, and p39, another activator, were not detected in bovine aortic EC, which suggests the existence of a novel CDK5 activator. Overall, this is the first study to find that CDK5 is a physiological kinase responsible for eNOS-Ser116 phosphorylation and regulation of NO production. Key Words: nitric oxide Ⅲ endothelial nitric oxide synthase Ⅲ cyclin-dependent kinase 5 Ⅲ endothelium Ⅲ phosphorylation Ⅲ signal transduction E ndothelial nitric oxide synthase (eNOS) is an essential enzyme responsible for the production of endotheliumderived nitric oxide (NO), which is a key molecule with multiple functions, including vascular homeostasis, angiogenesis, and cell cycle regulation. 1,2 The dysregulation of eNOS, therefore, contributes to the pathogenesis of certain diseases, such as atherosclerosis, hypertension, and cancer. 2 It is well known that eNOS is regulated at the level of its phosphorylation. 3,4 Several specific sites of phosphorylation have been identified, among which eNOS-Ser1179 (bovine sequence) and eNOS-Thr497 have been the most thoroughly evaluated. The phosphorylation of eNOS-Ser1179 increases NO production, 5-7 which is mediated by several specific protein kinases, including Akt, AMP-activated protein kinase, calmodulin-dependent kinase II, and protein kinase A (PKA). 8 -11 Conversely, the phosphorylation of eNOS-Thr497 decreases eNOS activity, 8,10 which is mediated by AMP-activated protein kinase 5 and protein kinase C (PKC). 10,12 This site is also dephosph...

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Regulation of Endothelial Nitric Oxide Synthase by Protein Kinase C

Cited by 103 publications

References 52 publications

Implication of PKC in the seasonal variation of the immune response of the hemocytes of Mytilus galloprovincialis Lmk. and its role in interleukin‐2‐induced nitric oxide synthesis

Implication of PKC in the seasonal variation of the immune response of the hemocytes of Mytilus galloprovincialis Lmk. and its role in interleukin‐2‐induced nitric oxide synthesis

Nitric Oxide Inhibition of Endothelin-1 Release in the Vasculature

Cyclin-Dependent Kinase 5 Phosphorylates Endothelial Nitric Oxide Synthase at Serine 116

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