Phosphorylated Endothelial NOS Ser1177 via the PI3K/Akt Pathway Is Depressed in the Brain of Stroke-Prone Spontaneously Hypertensive Rat

Yoshitomi, Hisae; Chen, Nansheng; Gao, Ming; Yamori, Yukio

doi:10.1016/j.jstrokecerebrovasdis.2010.01.014

Cited by 18 publications

(18 citation statements)

References 31 publications

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“…The present findings with Wortmannin and our previous findings, which demonstrated the ability of nonselective NOS (L-NAME) or selective nNOS (NPLA) inhibition to attenuate the peripheral NMDAR-pressor response and vascular NO generation 1 , suggest an important role for vascular PI3K/Akt in downstream activation of nNOS following vascular NMDAR activation. This notion is further supported by reported findings, including ours, which implicated PI3K in downstream NOS signaling, at least partly, via Akt phosphorylation 23, 32 . Nonetheless, the latter study identified PKC as an important intermediate signaling step in the PI3K activation of NOX in vitro.…”

Section: Discussionsupporting

confidence: 89%

Enhanced Vascular PI3K/Akt-NOX Signaling Underlies the Peripheral NMDAR-mediated Pressor Response in Conscious Rats

McGee

Abdel‐Rahman

2014

Journal of Cardiovascular Pharmacology

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The molecular mechanisms for peripheral N-Methyl-D-Aspartate receptor (NMDAR)-mediated vascular oxidative stress and pressor response are not known. We conducted integrative (in vivo) and ex vivo biochemical studies to test the hypothesis that ROS-dependent calcium influx, triggered by activation of vascular kinases, underlies the NMDAR-mediated pressor response. Pharmacological inhibition of PI3K/Akt (Wortmannin; 15 μg/kg), PKC (Chelerythrine; 5 mg/kg, i.v.), Ca2+ influx (nifedipine; 0.35 or 0.75 mg/kg) or NOX (apocynin; 5 mg/kg) attenuated the peripheral NMDAR-mediated pressor response in conscious male Sprague-Dawley rats. NMDAR activation enhanced the phosphorylation of Akt, ERK1, JNK and p38 (Western blot) and NADPH oxidase (NOX) activity in vascular tissues collected during the pressor response caused by NMDA infusion (180 μg/kg/min, 30 min). Further, ex vivo studies showed that wortmannin, chelerythrine or apocynin abrogated the NMDAR-mediated vascular NO and ROS generation and NOX activation in the vasculature. These findings implicate vascular PI3K/Akt-PKC signaling in the peripheral NMDAR-mediated increases in vascular NO and NOX activation (ROS), which ultimately lead to calcium influx and pressor response in conscious rats.

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Section: Discussionsupporting

confidence: 89%

Enhanced Vascular PI3K/Akt-NOX Signaling Underlies the Peripheral NMDAR-mediated Pressor Response in Conscious Rats

McGee

Abdel‐Rahman

2014

Journal of Cardiovascular Pharmacology

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“…It is well-established that eNOS is tightly regulated not only at the transcriptional level but also by certain post-transcriptional mechanisms (Vilahur et al, 2014; Yoshitomi et al, 2011). In the present study, we found that TE did not have an effect on the level of eNOS protein, but did markedly induce eNOS phosphorylation at Ser1177 from 15 to 60 min, suggesting that TE induced an increase in eNOS activity at the post-transcriptional level in HUVECs.…”

Section: Discussionmentioning

confidence: 99%

“…Besides, the activity of eNOS is also regulated by phosphorylation level. For example, eNOS phosphorylation at Ser1177 by phosphatidylinositol 3-kinase (PI3-K)-dependent Akt plays a critical role in eNOS activation (Yoshitomi et al, 2011). Thus, the current study was designed to investigate the effects and molecular mechanisms of TE on eNOS activity in endothelial cells by detecting the changes in both intracellular Ca 2+ concentration and Akt-dependent signal transduction pathways.…”

Section: Introductionmentioning

confidence: 99%

Mechanism of endothelial nitric oxide synthase phosphorylation and activation by tentacle extract from the jellyfishCyanea capillata

Wang

Liú

Wang

et al. 2017

PeerJ

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Our previous study demonstrated that tentacle extract (TE) from the jellyfish Cyanea capillata (C. capillata) could cause a weak relaxation response mediated by nitric oxide (NO) using isolated aorta rings. However, the intracellular mechanisms of TE-induced vasodilation remain unclear. Thus, this study was conducted to examine the role of TE on Akt/eNOS/NO and Ca2+ signaling pathways in human umbilical vein endothelial cells (HUVECs). Our results showed that TE induced dose- and time-dependent increases of eNOS activity and NO production. And TE also induced Akt and eNOS phosphorylation in HUVECs. However, treatment with specific PI3-kinase inhibitor (Wortmannin) significantly inhibited the increases in NO production and Akt/eNOS phosphorylation. In addition, TE also stimulated an increase in the intracellular Ca2+ concentration ([Ca2+]i), which was significantly attenuated by either IP3 receptor blocker (Heparin) or PKC inhibitor (PKC 412). In contrast, extracellular Ca2+-free, L-type calcium channel blocker (Nifedipine), or PKA inhibitor (H89) had no influence on the [Ca2+]i elevation. Since calcium ions also play a critical role in stimulating eNOS activity, we next explored the role of Ca2+ in TE-induced Akt/eNOS activation. In consistent with the attenuation of [Ca2+]i elevation, we found that Akt/eNOS phosphorylation was also dramatically decreased by Heparin or PKC 412, but not affected by Nifedipine or H89. However, the phosphorylation level could also be decreased by the removal of extracellular calcium. Taken together, our findings indicated that TE-induced eNOS phosphorylation and activation were mainly through PI3K/Akt-dependent, PKC/IP3R-sensitive and Ca2+-dependent pathways.

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“…Endothelial NOS derived NO participates in various physiological functions [67-69] including regulation of blood flow [67,90], arterial pressure [93], and signal transduction [94]. Similar to NOX, eNOS is also activated with the increased intracellular Ca 2+ and NO function involves the activation of ERK [64,68], NF-kB [40,84] and protein kinase B (Akt) [68,70,84]. In the reaction of O 2 .− , NO generates various other ROS/RNS that may cause protein damages [2,11], i.e., protein’s nitration [2,3], hence, play in SIC after TBI.…”

Section: Discussionmentioning

confidence: 99%

“…Several studies have implicated eNOS in the variety of physiological functions [67-69], and it’s up-regulation might be beneficial after TBI [61,63]. The activation of eNOS by phosphorylation (p-eNOS) has been linked to several cell signaling processes [64,70]. The bioavailability of eNOS derived NO depends on the rate of reaction with O 2 − (NO + O 2 .− → ONOO − ) that may be linked to NOX up-regulation.…”

Section: Introductionmentioning

confidence: 99%

A time course of NADPH-oxidase up-regulation and endothelial nitric oxide synthase activation in the hippocampus following neurotrauma

Ansari

Roberts

Scheff

2014

Free Radical Biology and Medicine

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Nicotinamide adenine dinucleotide phosphate oxidase (NADPH-oxidase; NOX) is a complex enzyme responsible for increased levels of reactive oxygen species (ROS), superoxide (O2.−). NOX derived O2.− is a key player in oxidative stress and inflammation mediated multiple secondary injury cascades (SIC) following traumatic brain injury (TBI). The O2.− reacts with nitric oxide (NO), produces various reactive nitrogen species (RNS), and contributes to apoptotic cell death. Following a unilateral cortical contusion, young adult rats were killed at various times post injury (1, 3, 6, 12, 24, 48, 72, and 96 h). Fresh tissue from the hippocampus was analyzed for NOX activity, and level of O2.−. In addition we evaluated the translocation of cytosolic NOX proteins (p67Phox, p47Phox and p40Phox) to the membrane, along with total NO and the activation (phosphorylation) of endothelial nitric oxide synthase (p-eNOS). Results show that both enzymes and levels of O2.− and NO have time dependent injury effects in the hippocampus. Translocation of cytosolic NOX proteins into membrane, NOX activity and O2.− were also increased in a time dependent fashion. Both, NOX activity and O2.− were increased at 6 h. Levels of p-eNOS increased within 1 h, with significant elevation of NO at 12 h post TBI. Levels of NO failed to show a significant association with p-eNOS, but did associate with O2.−. NOX up-regulation strongly associated with both the levels of O2.− and also total NO. The initial 12 hours post TBI are very important as a possible window of opportunity to interrupt SIC. It may be important to selectively target the translocation of cytosolic subunits for the modulation of NOX function.

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Phosphorylated Endothelial NOS Ser1177 via the PI3K/Akt Pathway Is Depressed in the Brain of Stroke-Prone Spontaneously Hypertensive Rat

Cited by 18 publications

References 31 publications

Enhanced Vascular PI3K/Akt-NOX Signaling Underlies the Peripheral NMDAR-mediated Pressor Response in Conscious Rats

Enhanced Vascular PI3K/Akt-NOX Signaling Underlies the Peripheral NMDAR-mediated Pressor Response in Conscious Rats

Mechanism of endothelial nitric oxide synthase phosphorylation and activation by tentacle extract from the jellyfishCyanea capillata

A time course of NADPH-oxidase up-regulation and endothelial nitric oxide synthase activation in the hippocampus following neurotrauma

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