Endothelial Nitric Oxide Synthase Phosphorylation at Threonine 495 and Mitochondrial Reactive Oxygen Species Formation in Response to a High H&lt;sub&gt;2&lt;/sub&gt;O&lt;sub&gt;2&lt;/sub&gt; Concentration

Guterbaum, Thomas; Braunstein, Thomas Hartig; Fossum, Anna; Holstein‐Rathlou, Niels‐Henrik; Torp‐Pedersen, Christian; Dominguez, Helena

doi:10.1159/000354225

Cited by 15 publications

(7 citation statements)

References 107 publications

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“…Besides serine 1177, other point of phosphorylation may modulate eNOS activity, such as Thr495 and Ser113 22 23 . Thus, we detected the effect of tBHQ on these sites.…”

Section: Resultsmentioning

confidence: 99%

RETRACTED ARTICLE: Tert-butylhydroquinone lowers blood pressure in AngII-induced hypertension in mice via proteasome-PTEN-Akt-eNOS pathway

Long

Luo

2016

Sci Rep

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Tert-butylhydroquinone (tBHQ), as an antioxidant, has been widely used for many years to prevent oxidization of food products. The aim of this study was to investigate whether tBHQ activates endothelial nitric oxide synthase (eNOS) to prevent endothelial dysfunction and lower blood pressure. The role of Akt in tBHQ-induced eNOS phosphorylation was examined in human umbilical vein endothelial cells (HUVEC) or in mice. tBHQ treatment of HUVEC increased both Akt-Ser473 phosphorylation, accompanied with increased eNOS-Ser1177 phosphorylation and NO release. Mechanically, pharmacologic or genetic inhibition of Akt abolished tBHQ-enhanced NO release and eNOS phosphorylation in HUVEC. Gain-function of PTEN or inhibition of 26S proteasome abolished tBHQ-enhanced Akt phosphorylation in HUVEC. Ex vivo analysis indicated that tBHQ improved Ach-induced endothelium-dependent relaxation in LPC-treated mice aortic arteries, which were abolished by inhibition of Akt or eNOS. In animal study, administration of tBHQ significantly increased eNOS-Ser1177 phosphorylation and acetylcholine-induced vasorelaxation, and lowered AngII-induced hypertension in wildtype mice, but not in mice deficient of Akt or eNOS. In conclusion, tBHQ via proteasome-dependent degradation of PTEN increases Akt phosphorylation, resulting in upregulation of eNOS-derived NO production and consequent improvement of endothelial function in vivo. In this way, tBHQ lowers blood pressure in hypertensive mice.

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“…Besides serine 1177, other point of phosphorylation may modulate eNOS activity, such as Thr495 and Ser113 22 23 . Thus, we detected the effect of tBHQ on these sites.…”

Section: Resultsmentioning

confidence: 99%

RETRACTED ARTICLE: Tert-butylhydroquinone lowers blood pressure in AngII-induced hypertension in mice via proteasome-PTEN-Akt-eNOS pathway

Long

Luo

2016

Sci Rep

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“…8a–c). Inhibition of other kinases implicated in eNOS phosphorylation (PKC, Erk) 40,41 did not counteract the effect of IL-17 on ACh-induced NO production (Fig. 8c).…”

Section: Resultsmentioning

confidence: 88%

Dietary salt promotes neurovascular and cognitive dysfunction through a gut-initiated TH17 response

et al. 2018

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A diet rich in salt is linked to an increased risk of cerebrovascular diseases and dementia, but it remains unclear how dietary salt harms the brain. We report that, in mice, excess dietary salt suppresses resting cerebral blood flow and endothelial function, leading to cognitive impairment. The effect depends on expansion of TH17 cells in the small intestine, resulting in a marked increase in plasma interleukin-17 (IL-17). Circulating IL-17, in turn, promotes endothelial dysfunction and cognitive impairment by the Rho kinase-dependent inhibitory phosphorylation of endothelial nitric oxide synthase and reduced nitric oxide production in cerebral endothelial cells. The findings reveal a new gut-brain axis linking dietary habits to cognitive impairment through a gut-initiated adaptive immune response compromising brain function via circulating IL-17. Thus, the TH17 cell-IL-17 pathway is a putative target to counter the deleterious brain effects induced by dietary salt and other diseases associated with TH17 polarization.

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“…Simvastatin was reported to increase NO formation, eNOS phosphorylation at Ser1177, to decrease phosphorylation at Thr495, and improve cardiac function in patients undergoing cardiac surgery [189]. Other therapeutic strategies for improvement of the ratio of phosphoThr495/phosphoSer1177 in eNOS were reported for exercise of mice [190,191], inhibition of the ROCK and ERK kinase pathways by MEKK1/2 inhibitor U0126 and ROCK inhibitor Y27632, thereby preventing the oxidative activation of PKC in human umbilical vein endothelial cells (HUVECs) [192]. Conversely, there seems to be a feedback mechanism to prevent over-activation of the “NO pathway”, as demonstrated by a decrease in Ser1177 and an increase in Thr495 phosphorylation of eNOS by chronic administration of high dose inorganic nitrate, which also resulted in impaired endothelium-dependent relaxation [193], providing a possible explanation as to why chronic NO donor therapy is not suitable for targeting the NO/cGMP pathway.…”

Section: “Redox Switches” In Endothelial Nitric Oxide Synthase (Enmentioning

confidence: 99%

New Therapeutic Implications of Endothelial Nitric Oxide Synthase (eNOS) Function/Dysfunction in Cardiovascular Disease

Daiber

Xia

Steven

et al. 2019

IJMS

206

129

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The Global Burden of Disease Study identified cardiovascular risk factors as leading causes of global deaths and life years lost. Endothelial dysfunction represents a pathomechanism that is associated with most of these risk factors and stressors, and represents an early (subclinical) marker/predictor of atherosclerosis. Oxidative stress is a trigger of endothelial dysfunction and it is a hall-mark of cardiovascular diseases and of the risk factors/stressors that are responsible for their initiation. Endothelial function is largely based on endothelial nitric oxide synthase (eNOS) function and activity. Likewise, oxidative stress can lead to the loss of eNOS activity or even “uncoupling” of the enzyme by adverse regulation of well-defined “redox switches” in eNOS itself or up-/down-stream signaling molecules. Of note, not only eNOS function and activity in the endothelium are essential for vascular integrity and homeostasis, but also eNOS in perivascular adipose tissue plays an important role for these processes. Accordingly, eNOS protein represents an attractive therapeutic target that, so far, was not pharmacologically exploited. With our present work, we want to provide an overview on recent advances and future therapeutic strategies that could be used to target eNOS activity and function in cardiovascular (and other) diseases, including life style changes and epigenetic modulations. We highlight the redox-regulatory mechanisms in eNOS function and up- and down-stream signaling pathways (e.g., tetrahydrobiopterin metabolism and soluble guanylyl cyclase/cGMP pathway) and their potential pharmacological exploitation.

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Endothelial Nitric Oxide Synthase Phosphorylation at Threonine 495 and Mitochondrial Reactive Oxygen Species Formation in Response to a High H<sub>2</sub>O<sub>2</sub> Concentration

Cited by 15 publications

References 107 publications

RETRACTED ARTICLE: Tert-butylhydroquinone lowers blood pressure in AngII-induced hypertension in mice via proteasome-PTEN-Akt-eNOS pathway

RETRACTED ARTICLE: Tert-butylhydroquinone lowers blood pressure in AngII-induced hypertension in mice via proteasome-PTEN-Akt-eNOS pathway

Dietary salt promotes neurovascular and cognitive dysfunction through a gut-initiated TH17 response

New Therapeutic Implications of Endothelial Nitric Oxide Synthase (eNOS) Function/Dysfunction in Cardiovascular Disease

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