scholarly journals Impressic Acid, a Lupane-Type Triterpenoid from Acanthopanax koreanum, Attenuates TNF-α-Induced Endothelial Dysfunction via Activation of eNOS/NO Pathway

2019 ◽  
Vol 20 (22) ◽  
pp. 5772 ◽  
Author(s):  
Sun Woo Jin ◽  
Hoa Thi Pham ◽  
Jae Ho Choi ◽  
Gi Ho Lee ◽  
Eun Hee Han ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Endothelial Cells ◽  
Vascular Endothelium ◽  
Vascular Function ◽  
Vascular Inflammation ◽  
Systemic Blood Pressure ◽  
No Production ◽  
Acanthopanax Koreanum ◽  
Tnf Α ◽  
Enos Phosphorylation

Atherosclerosis is one of the most reported diseases worldwide, and extensive research and trials are focused on the discovery and utilizing for novel therapeutics. Nitric oxide (NO) is produced mainly by endothelial nitric oxide synthase (eNOS) and it plays a key role in regulating vascular function including systemic blood pressure and vascular inflammation in vascular endothelium. In this study hypothesized that Impressic acid (IPA), a component isolated from Acanthopanax koreanum, acts as an enhancer of eNOS activity and NO production. IPA treatment induced eNOS phosphorylation and NO production, which was correlated with eNOS phosphorylation via the activation of JNK1/2, p38 MAPK, AMPK, and CaMKII. In addition, the induction of eNOS phosphorylation by IPA was attenuated by pharmacological inhibitor of MAPKs, AMPK, and CaMKII. Finally, IPA treatment prevented the adhesion of TNF-α-induced monocytes to endothelial cells and suppressed the TNF-α-stimulated ICAM-1 expression via activation of NF-κB, while treatment with L-NAME, the NOS inhibitor, reversed the inhibitory effect of IPA on TNF-α-induced ICAM-1 expression via activation of NF-κB. Taken together, these findings show that IPA protects against TNF-α-induced vascular endothelium dysfunction through attenuation of the NF-κB pathway by activating eNOS/NO pathway in endothelial cells.

scholarly journals Anti-Vascular Inflammatory Effect of Ethanol Extract from Securinega suffruticosa in Human Umbilical Vein Endothelial Cells

Nutrients ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 3448
Author(s):  
Byung Hyuk Han ◽  
Chun Ho Song ◽  
Jung Joo Yoon ◽  
Hye Yoom Kim ◽  
Chang Seob Seo ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Endothelial Cells ◽  
Cell Adhesion ◽  
Protective Effect ◽  
Adhesion Molecule ◽  
Umbilical Vein ◽  
Vascular Inflammation ◽  
No Production ◽  
Tnf Α ◽  
Umbilical Vein Endothelial Cells

Securiniga suffruticosa is known as a drug that has the effect of improving the blood circulation and relaxing muscles and tendons, thereby protects and strengthen kidney and spleen. Therefore, in this study, treatment of Securiniga suffruticosa showed protective effect of inhibiting the vascular inflammation in human umbilical vein endothelial cells (HUVECs) by inducing nitric oxide (NO) production and endothelial nitric oxide synthase (eNOS) coupling pathway. In this study, Securiniga suffruticosa suppressed TNF-α (Tumor necrosis factor–α) induced protein and mRNA levels of cell adhesion molecules such as intracellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and Interleukin-6 (IL-6). Pretreatment of HUVEC with Securiniga suffruticosa decreased the adhesion of HL-60 cells to Ox-LDL (Oxidized Low-Density-Lipoprotein)-induced HUVEC. Moreover, Securiniga suffruticosa inhibited TNF-α induced intracellular reactive oxygen species (ROS) production. Securiniga suffruticosa also inhibited phosphorylation of IκB-α in cytoplasm and translocation of NF-κB (Nuclear factor-kappa B) p65 to the nucleus. Securiniga suffruticosa increased NO production, as well increased the phosphorylation of eNOS and Akt (protein kinase B) which are related with NO production. In addition, Securiniga suffruticosa increased the protein expression of GTPCH (Guanosine triphosphate cyclohydrolase Ⅰ) and the production of BH4 in HUVEC which are related with eNOS coupling pathway. In conclusion, Securiniga suffruticosa has a protective effect against vascular inflammation and can be a potential therapeutic agent for early atherosclerosis.

Abstract 482: IDH2 Deficiency Induces Oxidative Stress and Vascular Inflammation

2017 ◽  
Vol 37 (suppl_1) ◽  
Author(s):  
Seonhee Kim ◽  
Su-jeong Choi ◽  
Harsha Nagar ◽  
Shuyu Piao ◽  
Ikjun Lee ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Endothelial Cells ◽  
Mitochondrial Dysfunction ◽  
Vascular Function ◽  
Vascular System ◽  
Vascular Inflammation ◽  
No Production ◽  
Mitochondrial Superoxide ◽  
Isocitrate Dehydrogenase 2 ◽  
Enos Phosphorylation

Isocitrate dehydrogenase 2 (IDH2) plays an essential role protecting cells against oxidative stress-induced damage. A deficiency in IDH2 leads to mitochondrial dysfunction and the production of reactive oxygen species (ROS) in cardiomyocytes and endothelial cells. However, the physiological function of IDH2 in vascular system is mostly unknown In this study, we investigated whether IDH2 knockdown causes mitochondrial dysfunction and vascular inflammation in vitro and in vivo . IDH2 knockdown decreased the expression of mitochondrial oxidative phosphorylation (OXPHOS) complexes I, II and III, which lead to increased mitochondrial superoxide. In addition, the levels of fission and fusion proteins (Mfn-1, OPA-1, and Drp-1) were significantly altered and MnSOD expression also was decreased by IDH2 knockdown. Furthermore, knockdown of IDH2 decreased eNOS phosphorylation and nitric oxide (NO) concentration in endothelial cells. Interestingly, treatment with Mito-TEMPO, a mitochondrial-specific superoxide scavenger, recovered mitochondrial fission-fusion imbalance and blunted mitochondrial superoxide production, and reduced the IDH2 knockdown-induced decrease in MnSOD expression, eNOS phosphorylation and NO production in endothelial cells. Endothelium-dependent vasorelaxation was impaired, and the concentration of bioavailable NO decreased in the aortic ring in IDH2 knockout mice. These findings suggest that IDH2 deficiency induces endothelial dysfunction through the induction of dynamic mitochondrial changes and impairment in vascular function. Key words: IDH2, mitochondria, endothelial cells, ROS

Laminar Flow on Endothelial Cells Suppresses eNOS O-GlcNAcylation to Promote eNOS Activity

2021 ◽  
Author(s):  
Sarah Basehore ◽  
Samantha Bohlman ◽  
Callie Weber ◽  
Swathi Swaminathan ◽  
Yuji Zhang ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Endothelial Cells ◽  
Shear Stress ◽  
Laminar Flow ◽  
No Production ◽  
Disturbed Flow ◽  
Enos Activity ◽  
Enos Phosphorylation ◽  
Steady Laminar ◽  
In Cells

Rationale: In diabetic animals as well as high glucose cell culture conditions, endothelial nitric oxide synthase (eNOS) is heavily O-GlcNAcylated, which inhibits its phosphorylation and nitric oxide (NO) production. It is unknown, however, whether varied blood flow conditions, which affect eNOS phosphorylation, modulate eNOS activity via O-GlcNAcylation-dependent mechanisms. Objective: The goal of this study was to test if steady laminar flow, but not oscillating disturbed flow, decreases eNOS O-GlcNAcylation, thereby elevating eNOS phosphorylation and NO production. Methods and Results: Human umbilical vein endothelial cells (HUVEC) were exposed to either laminar flow (20 dynes/cm2 shear stress) or oscillating disturbed flow (4{plus minus}6 dynes/cm2 shear stress) for 24 hours in a cone-and-plate device. eNOS O-GlcNAcylation was almost completely abolished in cells exposed to steady laminar but not oscillating disturbed flow. Interestingly, there was no change in protein level or activity of key O-GlcNAcylation enzymes (OGT, OGA, or GFAT). Instead, metabolomics data suggest that steady laminar flow decreases glycolysis and hexosamine biosynthetic pathway (HBP) activity, thereby reducing UDP-GlcNAc pool size and consequent O-GlcNAcylation. Inhibition of glycolysis via 2-deoxy-2-glucose (2-DG) in cells exposed to disturbed flow efficiently decreased eNOS O-GlcNAcylation, thereby increasing eNOS phosphorylation and NO production. Finally, we detected significantly higher O-GlcNAcylated proteins in endothelium of the inner aortic arch in mice, suggesting that disturbed flow increases protein O-GlcNAcylation in vivo. Conclusions: Our data demonstrate that steady laminar but not oscillating disturbed flow decreases eNOS O-GlcNAcylation by limiting glycolysis and UDP-GlcNAc substrate availability, thus enhancing eNOS phosphorylation and NO production. This research shows for the first time that O-GlcNAcylation is regulated by mechanical stimuli, relates flow-induced glycolytic reductions to macrovascular disease, and highlights targeting HBP metabolic enzymes in endothelial cells as a novel therapeutic strategy to restore eNOS activity and prevent EC dysfunction in cardiovascular disease.

scholarly journals Cadmium reduces nitric oxide production by impairing phosphorylation of endothelial nitric oxide synthase

2008 ◽  
Vol 86 (1) ◽  
pp. 1-10 ◽  
Author(s):  
Syamantak Majumder ◽  
Ajit Muley ◽  
Gopi Krishna Kolluru ◽  
Samir Saurabh ◽  
K. P. Tamilarasan ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Endothelial Cells ◽  
Endothelial Function ◽  
Egg Yolk ◽  
Cellular Migration ◽  
No Production ◽  
Enos Phosphorylation ◽  
Low Levels ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide

Cadmium (Cd) perturbs vascular health and interferes with endothelial function. However, the effects of exposing endothelial cells to low doses of Cd on the production of nitric oxide (NO) are largely unknown. The objective of the present study was to evaluate these effects by using low levels of CdCl2 concentrations, ranging from 10 to 1000 nmol/L. Cd perturbations in endothelial function were studied by employing wound-healing and MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assays. The results suggest that a CdCl2 concentration of 100 nmol/L maximally attenuated NO production, cellular migration, and energy metabolism in endothelial cells. An egg yolk angiogenesis model was employed to study the effect of Cd exposure on angiogenesis. The results demonstrate that NO supplementation restored Cd-attenuated angiogenesis. Immunofluorescence, Western blot, and immuno-detection studies showed that low levels of Cd inhibit NO production in endothelial cells by blocking eNOS phosphorylation, which is possibly linked to processes involving endothelial function and dysfunction, including angiogenesis.

scholarly journals Androgen Receptor-Dependent Activation of Endothelial Nitric Oxide Synthase in Vascular Endothelial Cells: Role of Phosphatidylinositol 3-Kinase/Akt Pathway

Endocrinology ◽  
2010 ◽  
Vol 151 (4) ◽  
pp. 1822-1828 ◽  
Author(s):  
Jing Yu ◽  
Masahiro Akishita ◽  
Masato Eto ◽  
Sumito Ogawa ◽  
Bo-Kyung Son ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Endothelial Cells ◽  
Androgen Receptor ◽  
Pi3 Kinase ◽  
Maximal Response ◽  
No Production ◽  
Dependent Manner ◽  
Small Interference Rna ◽  
Enos Phosphorylation ◽  
Interference Rna

The mechanisms of testosterone-induced vasodilatation are not fully understood. This study investigated the effect of testosterone on nitric oxide (NO) synthesis and its molecular mechanism using human aortic endothelial cells (HAEC). Testosterone at physiological concentrations (1–100 nm) induced a rapid (15–30 min) increase in NO production, which was associated with phosphorylation and activation of endothelial NO synthase (eNOS). Then, the involvement of the androgen receptor (AR), which is abundantly expressed in HAEC, was examined. The effect of testosterone on eNOS activation and NO production were abolished by pretreatment with an AR antagonist nilutamide and by transfection with AR small interference RNA. In contrast, testosterone-induced eNOS phosphorylation was unchanged by pretreatment with an aromatase inhibitor or by transfection with ERα small interference RNA. 5α-Dihydrotestosterone, a nonaromatizable androgen, also stimulated eNOS phosphorylation. Next, the signaling cascade that leads to eNOS phosphorylation was explored. Testosterone stimulated rapid phosphorylation of Akt in a time- and dose-dependent manner, with maximal response at 15–60 min. The rapid phosphorylation of eNOS or NO production induced by testosterone was inhibited by Akt inhibitor SH-5 or by phosphatidylinositol (PI) 3-kinase inhibitor wortmannin. Co-immunoprecipitation assays revealed a testosterone-dependent interaction between AR and the p85α subunit of PI3-kinase. In conclusion, testosterone rapidly induces NO production via AR-dependent activation of eNOS in HAEC. Activation of PI3-kinase/Akt signaling and the direct interaction of AR with p85α are involved, at least in part, in eNOS phosphorylation.

Deferiprone increases endothelial nitric oxide synthase phosphorylation and nitric oxide production

2018 ◽  
Vol 96 (9) ◽  
pp. 879-885 ◽  
Author(s):  
Thanaporn Sriwantana ◽  
Pornpun Vivithanaporn ◽  
Kittiphong Paiboonsukwong ◽  
Krit Rattanawonsakul ◽  
Sirada Srihirun ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Blood Pressure ◽  
Endothelial Cells ◽  
Endothelial Function ◽  
Healthy Subjects ◽  
Iron Chelation ◽  
No Production ◽  
Hemoglobin E ◽  
Enos Phosphorylation

Iron chelation can improve endothelial function. However, effect on endothelial function of deferiprone has not been reported. We hypothesized deferiprone could promote nitric oxide (NO) production in endothelial cells. We studied effects of deferiprone on blood nitrite and blood pressure after single oral dose (25 mg/kg) in healthy subjects and hemoglobin E/β-thalassemia patients. Further, effects of deferiprone on NO production and endothelial NO synthase (eNOS) phosphorylation in primary human pulmonary artery endothelial cells (HPAEC) were investigated in vitro. Blood nitrite levels were higher in patients with deferiprone therapy than those without deferiprone (P = 0.023, n = 16 each). Deferiprone increased nitrite in plasma and whole blood of healthy subjects (P = 0.002 and 0.044) and thalassemia patients (P = 0.003 and 0.046) at time 180 min (n = 20 each). Asymptomatic reduction in diastolic blood pressure (P = 0.005) and increase in heart rate (P = 0.009) were observed in healthy subjects, but not in thalassemia patients. In HPAEC, deferiprone increased cellular nitrite and phospho-eNOS (Ser1177) (P = 0.012 and 0.035, n = 6) without alteration in total eNOS protein and mRNA. We conclude that deferiprone can induce NO production by enhancing eNOS phosphorylation in endothelial cells.

Abstract 335: Atheroma-specific Delivery of Synthetic High-density Lipoprotein Containing Sphingosine-1-phosphate for Modulation of Vascular Inflammation.

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Emily E Morin ◽  
Yanhong Guo ◽  
Rui Kuai ◽  
Gergely Lautner ◽  
Mark E Meyerhoff ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Endothelial Cells ◽  
Vascular Inflammation ◽  
The Body ◽  
Saline Control ◽  
No Production ◽  
No Release ◽  
Sphingosine 1 Phosphate ◽  
Anti Inflammatory

Introduction: Sphingosine-1-phosphate (S1P) is a potent anti-inflammatory signaling lipid carried in the body by circulating HDL. HDL has been shown to exhibit anti-inflammatory activities through activation of endothelial nitric oxide synthase (eNOS) and subsequent production and release of nitric oxide (NO) by endothelial cells. Objective: The aim of this study is to use synthetic HDL particles to selectively deliver S1P to the site of arterial plaques in order to exert anti-inflammatory activity and modulate the progression of atherosclerosis. Methods/Results: Synthetic HDL (sHDL) particles were prepared using the ApoA1 mimetic peptide 22A (PVLDLFRELLNELLEALKQKLK), dipalmitoylphosphatidylcholine (DPPC) and sphingomyelin. We also prepared sHDL containing either the hydrophobic dye, DiD, or S1P to assess the capability of sHDL to effectively reach atheroma site and induce nitric oxide (NO) release, respectively. The purity of all particles was determined to be > 97% and average particle size was 9.6 ± 0.4 nm for all preparations. To measure sHDL accumulation in the plaque, ApoE -/- mice were intravenously injected with 0.2 mg/kg HDL-DiD. Whole aortas were excised and analysed by IVUS imaging system, revealing significant accumulation of sHDL-DiD in the atherosclerotic lesions. We then tested the ability of sHDL to deliver S1P in vitro and induce NO production by treating human umbilical vein endothelial cells (HUVEC) with 1 mg/mL of 22A-DPPC-sHDL containing 0, 0.05, 0.5, or 5 nmol/mL of S1P using free 22A peptide (1 mg/mL) and saline as controls, and analyzing media by ozone chemiluminescence. Blank sHDL particles increased NO production two-fold over controls (0.27 ± 0.02 μM for 22A-DPPC-sHDLDL, 0.13 ± 0.01 μM PBS and 0.14 ± 0.02 μM for 22A peptide), while HDL-S1P further increased NO release: 0.35 ± 0.03, 0.44 ± 0.01, and 0.59 ± 0.01 μM for HDL with 0.05, 0.5, and 5 nmol/mL S1P, respectively. Conclusions: Our studies show that HDL is capable of delivering hydrophobic cargo to atherosclerotic plaques, making HDL a promising platform to deliver S1P for modulation vascular inflammation and atherosclerosis. In vitro studies have revealed that HDL-S1P is able to increase NO production 2 to 4-fold over saline control setting the basis for future in vivo studies.

Tumor necrosis factor-α reduces argininosuccinate synthase expression and nitric oxide production in aortic endothelial cells

2007 ◽  
Vol 293 (2) ◽  
pp. H1115-H1121 ◽  
Author(s):  
Bonnie L. Goodwin ◽  
Laura C. Pendleton ◽  
Monique M. Levy ◽  
Larry P. Solomonson ◽  
Duane C. Eichler
Keyword(s):  
Nitric Oxide ◽  
Endothelial Cells ◽  
Elevated Serum ◽  
Proximal Promoter ◽  
No Production ◽  
Aortic Endothelial Cells ◽  
Tnf Α ◽  
Argininosuccinate Synthase ◽  
Endothelial Nitric Oxide ◽  
Aortic Endothelial

Endothelial dysfunction associated with elevated serum levels of TNF-α observed in diabetes, obesity, and congenital heart disease results, in part, from the impaired production of endothelial nitric oxide (NO). Cellular NO production depends absolutely on the availability of arginine, substrate of endothelial nitric oxide synthase (eNOS). In this report, evidence is provided demonstrating that treatment with TNF-α (10 ng/ml) suppresses not only eNOS expression but also the availability of arginine via the coordinate suppression of argininosuccinate synthase (AS) expression in aortic endothelial cells. Western blot and real-time RT-PCR demonstrated a significant and dose-dependent reduction of AS protein and mRNA when treated with TNF-α with a corresponding decrease in NO production. Reporter gene analysis demonstrated that TNF-α suppresses the AS proximal promoter, and EMSA analysis showed reduced binding to three essential Sp1 elements. Inhibitor studies suggested that the repression of AS expression by TNF-α may be mediated, in part, via the NF-κB signaling pathway. These findings demonstrate that TNF-α coordinately downregulates eNOS and AS expression, resulting in a severely impaired citrulline-NO cycle. The downregulation of AS by TNF-α is an added insult to endothelial function because of its important role in NO production and in endothelial viability.

Clinopodium chinense Attenuates Palmitic Acid-Induced Vascular Endothelial Inflammation and Insulin Resistance through TLR4-Mediated NF-κB and MAPK Pathways

2019 ◽  
Vol 47 (01) ◽  
pp. 97-117 ◽  
Author(s):  
Xiaoji Shi ◽  
Shanshan Wang ◽  
Huiling Luan ◽  
Dina Tuerhong ◽  
Yining Lin ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Insulin Resistance ◽  
Endothelial Cells ◽  
Endothelial Dysfunction ◽  
Palmitic Acid ◽  
Vascular Endothelium ◽  
Interleukin 1 ◽  
No Production ◽  
Vascular Endothelial ◽  
Mapk Pathways

Elevated palmitic acid (PA) levels are associated with the development of inflammation, insulin resistance (IR) and endothelial dysfunction. Clinopodium chinense (Benth.) O. Kuntze has been shown to lower blood glucose and attenuate high glucose-induced vascular endothelial cells injury. In the present study we investigated the effects of ethyl acetate extract of C. chinense (CCE) on PA-induced inflammation and IR in the vascular endothelium and its molecular mechanism. We found that CCE significantly inhibited PA-induced toll-like receptor 4 (TLR4) expression in human umbilical vein endothelial cells (HUVECs). Consequently, this led to the inhibition of the following downstream adapted proteins myeloid differentiation primary response gene 88, Toll/interleukin-1 receptor domain-containing adaptor-inducing interferon-[Formula: see text] and TNF receptor-associated factor 6. Moreover, CCE inhibited the phosphorylation of Ikappa B kinase [Formula: see text], nuclear factor kappa-B (NF-[Formula: see text]B), c-Jun N-terminal kinase, extracellular regulated protein kinases, p38-mitogen-activated protein kinase (MAPK) and subsequently suppressed the release of tumor necrosis factor-[Formula: see text], interleukin-1[Formula: see text] (IL-1[Formula: see text]) and IL-6. CCE also inhibited IRS-1 serine phosphorylation and ameliorated insulin-mediated tyrosine phosphorylation of IRS-1. Moreover, CCE restored serine/threonine kinase and endothelial nitric oxide synthase (eNOS) activation and thus increased insulin-mediated nitric oxide (NO) production in PA-treated HUVECs. This led to reverse insulin mediated endothelium-dependent relaxation, eNOS phosphorylation and NO production in PA-treated rat thoracic aortas. These results suggest that CCE can significantly inhibit the inflammatory response and alleviate impaired insulin signaling in the vascular endothelium by suppressing TLR4-mediated NF-[Formula: see text]B and MAPK pathways. Therefore, CCE can be considered as a potential therapeutic candidate for endothelial dysfunction associated with IR and diabetes.

scholarly journals MAGI1 Mediates eNOS Activation and NO Production in Endothelial Cells in Response to Fluid Shear Stress

Cells ◽  
2019 ◽  
Vol 8 (5) ◽  
pp. 388 ◽  
Author(s):  
Kedar Ghimire ◽  
Jelena Zaric ◽  
Begoña Alday-Parejo ◽  
Jochen Seebach ◽  
Mélanie Bousquenaud ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Endothelial Cells ◽  
Shear Stress ◽  
Endothelial Cell ◽  
Protein Kinase ◽  
Fluid Shear Stress ◽  
Adaptor Protein ◽  
No Production ◽  
Fluid Shear ◽  
Enos Phosphorylation

Fluid shear stress stimulates endothelial nitric oxide synthase (eNOS) activation and nitric oxide (NO) production through multiple kinases, including protein kinase A (PKA), AMP-activated protein kinase (AMPK), AKT and Ca2+/calmodulin-dependent protein kinase II (CaMKII). Membrane-associated guanylate kinase (MAGUK) with inverted domain structure-1 (MAGI1) is an adaptor protein that stabilizes epithelial and endothelial cell-cell contacts. The aim of this study was to assess the unknown role of endothelial cell MAGI1 in response to fluid shear stress. We show constitutive expression and co-localization of MAGI1 with vascular endothelial cadherin (VE-cadherin) in endothelial cells at cellular junctions under static and laminar flow conditions. Fluid shear stress increases MAGI1 expression. MAGI1 silencing perturbed flow-dependent responses, specifically, Krüppel-like factor 4 (KLF4) expression, endothelial cell alignment, eNOS phosphorylation and NO production. MAGI1 overexpression had opposite effects and induced phosphorylation of PKA, AMPK, and CAMKII. Pharmacological inhibition of PKA and AMPK prevented MAGI1-mediated eNOS phosphorylation. Consistently, MAGI1 silencing and PKA inhibition suppressed the flow-induced NO production. Endothelial cell-specific transgenic expression of MAGI1 induced PKA and eNOS phosphorylation in vivo and increased NO production ex vivo in isolated endothelial cells. In conclusion, we have identified endothelial cell MAGI1 as a previously unrecognized mediator of fluid shear stress-induced and PKA/AMPK dependent eNOS activation and NO production.

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