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"It has been reported that eNOS phosphorylation by PI3K and Akt pathway is required for efficient NO production [XREF_BIBR, XREF_BIBR], after phosphorylated at Ser 473 by PI3K, Akt in turn phosphorylates eNOS at Ser 1177 and thereby increases eNOS activity, and finally enhances NO production."
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"XREF_BIBR, XREF_BIBR Under these conditions, activation of GPER by G-1 resulted in reduced myocardial expression of proinflammatory cytokines (IL-1beta, IL-6 and tumor necrosis factor), 145 increased activation of Akt, 132 ERK1/2, XREF_BIBR, XREF_BIBR increased phosphorylation of eNOS 132 and decreased mitochondrial permeability."
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"Activation of VEGFR2 in endothelial cells (by VEGF binding) results in the Akt-dependent phosphorylation of eNOS at Ser 1177 xref , xref , while VEGF treatment of BAECs resulted in the phosphorylation of eNOS at Ser 617 and Ser 635 (equivalent to human Ser 615 and Ser 633 ) xref ."
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"Akt, a serine/threonine kinase, phosphorylates eNOS thereby activating the
enzyme. xref Phosphorylation
of eNOS at Ser 1177 residue is a critical requirement for eNOS activation,
whereas phosphorylation at Thr 495 residue leads to inactivation of the
enzyme. xref Here we
demonstrated that ethanol had no effect on the Akt/eNOS phosphorylation, which
corroborated the observation that ethanol intake did not alter the concentration of
nitrate in the rat MAB."
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"Endothelium-derived nitric oxide is another important promoter of VP and is produced by eNOS. xref , xref Phosphorylation of eNOS by AKT is required for efficient production of nitric oxide. xref However, eNOS inhibitors had no effect on Fg-induced VP, suggesting that Fg/AKT-induced VP is independent of eNOS pathway."
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"Since it has been well established that PI 3 -kinase and Akt pathway regulates eNOS activity through phosphorylation at the pro active site (Ser1177), a PI 3 -kinase inhibitor LY-294002 was used to test whether LA induced eNOS phosphorylation is mediated by PI 3 -kinase and Akt pathway."
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"Although NO production depends on Ca level, an additional mechanism of eNOS phosphorylation by PKA, protein kinase B (PKB), and cyclic guanosine monophosphate (cGMP)-dependent protein kinase II (cGKII) may compensate for NO production in the event of intercellular Ca reduction [81,82]."
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"It was also reported that production of NO in response to fluid shear stress in cultured endothelial cells was controlled by Akt dependent phosphorylation of eNOS, (Dimmeler et al. 1999) and another study demonstrated that shear stress induces eNOS phosphorylation predominantly through a protein kinase A dependent, Akt independent mechanism (Boo 2006)."
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"The stimulatory phosphorylation of eNOS residues Ser 1177 and Ser 617 occur in response to flow shear stress that activates phosphatidyl-inositol 3-kinase (PI3K) and its downstream serine/threonine protein kinase, Akt, which in turn phosphorylates eNOS (PI3K-Akt-eNOS pathway) XREF_BIBR, XREF_BIBR, XREF_BIBR."
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"In vitro, acute insulin signaling activated eNOS phosphorylation mediated by PI3K and Akt signaling in LECs, but prolonged hyperinsulinemia and hyperglycemia promoted insulin resistance, impaired PI3K/Akt/eNOS signaling, mitochondrial function, and NO bioavailability, and also increased lymphatic permeability."
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"PI3K/Akt signaling pathway is a predominantly cell-survival and cytoprotective pathway in many cell types. xref APC activates the PI3K/Akt pathway in the endothelial cells in EPCR-and PAR1-dependent manner. xref Akt directly phosphorylates GSK3β and eNOS, which promote cell survival and barrier stabilization pathways. xref , xref Our present data show that FVIIa activates the Akt pathway and induces the phosphorylation of Akt substrates GSK3ß and eNOS."
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"VEGFR2 is a receptor tyrosine kinase that can activate protein kinase B (Akt) that phosphorylates eNOS to maintain the differentiation of LSECs.36 Therefore, Notch activation could skew down eNOS‐sGC signaling through two mechanisms, in LSECs: directly down‐regulating eNOS expression and reducing eNOS phosphorylation by down‐regulating its upstream kinases, VEGFR2."
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"We therefore reasoned that the dissociation of eNOS phosphorylation and NO synthesis specific to insulin stimulated cells implies that stimulation of Akt and subsequent phosphorylation of eNOS may be required, yet insufficient, for insulin stimulated NO synthesis in cells cultured in high glucose."
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"Together, our observations indicated that the anti‐arrhythmic effect of clenbuterol may, in part, be associated with the preservation of the phosphorylated Cx43 and Cx43 distribution by NO during ischemia/reperfusion‐induced injury.Phosphorylation of eNOS by Akt plays a crucial part in protecting against myocardial ischemia/reperfusion injuries [32]."
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"Statins also increase eNOS activity by post-translational activation of the phosphatidylinositol 3-kinase/protein kinase Akt (PI3k/Akt) pathway as eNOS is phosphorylated by Akt. xref Inhibition of the Rho/ROCK pathway activates the PI3k/Akt pathway and cardioprotection. xref , xref ROCK is a negative regulator of the Akt pathway, possibly through activation of phosphatase and tensin homologue. xref "
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"Akt kinase has a significant action in the cardiovascular system, such as proliferation and cell growth via mTORC1, promotes cell survival via caspase-9, YAP, Bcl-2, and Bcl-x activities, and angiogenesis, vasorelaxation, and cell metabolism via VEGF secretion and mediates eNOS phosphorylation (Figure 1)."
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"Moreover, a link between the inhibition of mTOR and the activation of eNOS had been suggested by studies showing that Akt, which phosphorylates eNOS and increases NO production, can be activated by rapamycin treatment [ xref ] and conversely, that activation of mTOR results in Akt inhibition [ xref ]."
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"It also phosphorylates and activates IKK, which leads to activation of NF-κB. Endothelial nitric oxide synthase (eNOS) is also phosphorylated by Akt, thereby enhancing the production and release of nitric oxide (NO), a prominent vasodilator and anti-inflammatory molecule (Boucher et al., 2014)."
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"Akt phosphorylates and activates eNOS, rendering the enzyme 40% more sensitive to CaM (changing the relative K0.5, the concentration of added CaM required for halfmaximal enzyme activity read from the dose response curves, from 135 to 85 nM) and increasing the maximum activity (Vmax) by 50%."
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"In endothelial cells, Akt phosphorylates eNOS directly which promotes cell survival by nitrosylating the reactive cysteine residue in caspases ( xref ) and critically regulates apoptosis in endothelial cells including activation of the pro-apoptotic proteins Bax and caspases 3 and 9 ( xref )."
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"Selective inhibitors (i) of phosphodiesterase type 5 (PDE5) in men with ED and VRFs are effective in treating ED, while improving the endothelial function at the brachial arteries and reducing the biochemical measures of endothelial cell damage/dysfunction. xref xref xref xref xref xref These agents competitively inhibit cyclic guanosine 5’- monophosphate hydrolysis by PDE5, thereby fostering NO-dependent cyclic guanosine 5’- monophosphate accumulation and the consequent relaxation of vascular smooth muscle cells. xref It is suggested that the beneficial effect of PDE5i on endothelial cells is related to the stimulation of the synthesis and transcription of endothelial NO synthase mRNA and protein and to Akt-dependent eNOS phosphorylation. xref xref eNOS-derived NO plays an essential role in the mobilization and function of bone marrow-derived PGCs; xref whereas, the activation of the intracellular Akt pathway increases the number of ex vivo expanded CACs by modulating the survival and/or proliferation of freshly isolated cells. xref xref PDE5i treatment of men with ED and VRFs is associated with an increased number of circulating PGCs and ex vivo expanded CACs. xref xref "
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"Decreased expression of endothelial NO synthase (eNOS) protein, decreased phosphorylation of eNOS by the serine-threonine kinase AKT, the presence of inhibitory substances (e.g., asymmetric dimethylarginine, ADMA), and hyporesponsiveness to NO underlie this endothelial dysfunction [ xref – xref ]."
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"XREF_BIBR, XREF_BIBR The effects of statins on eNOS expression are not reversed by FPP or LDL-C, indicating that the effect is likely mediated through the geranylgeranylation of RhoA and ROCK signaling 80 Statins also increase eNOS activity by post-translational activation of the phosphatidylinositol 3-kinase/protein kinase Akt (PI3k and Akt) pathway as eNOS is phosphorylated by Akt."
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"Later on, a sequence of non classical, non genomic, E2 receptor membrane actions involving rapid signal-transduction pathways was detailed, including activation of phosphatidylinositol 3-kinase, protein kinase B (Akt) cascade generation and, by Galphai protein interaction, long lasting estrogen mediated eNOS phosphorylation and genomic NO production XREF_BIBR, XREF_BIBR, XREF_BIBR."
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"In endothelial cells, Akt phosphorylates eNOS directly which promotes cell survival by nitrosylating the reactive cysteine residue in caspases (13) and critically regulates apoptosis in endothelial cells including activation of the pro-apoptotic proteins Bax and caspases 3 and 9 (32)."
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"We and others have demonstrated that eNOS phosphorylation in sinusoidal endothelial cells is abnormal after injury, likely due to abnormal post-translational modification (s) (XREF_FIG); for example, Akt phosphorylation and subsequent activation of eNOS enzymatic activity are reduced in injured compared to normal sinusoidal endothelial cells."
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"This is believed to result from the anti-inflammatory effects of endothelially derived nitric oxide, due to a preconditioning induced Akt dependent phosphorylation of endothelial NOS (Hashiguchi et al., 2004, Furuya et al., 2005) that enhances nitric oxide activity (Puisieux et al., 2000, Furuya et al., 2005)."
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"NO appears to have two roles in the development of an erection : a rapid, brief, calcium dependent activation of nNOS initiates the erectile process, whereas PI3K and Akt dependent phosphorylation of eNOS results in sustained NO production and thereby enables full erection attainment [XREF_BIBR, XREF_BIBR]."
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"The inability of VEGFR2 neutralization to affect flow induced Akt phosphorylation despite attenuating eNOS phosphorylation is consistent with the findings by Jo and colleagues, who demonstrated that shear stress stimulates phosphorylation of eNOS by an Akt independent mechanism [XREF_BIBR]."
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"Regarding the potential of m6A as a therapeutic target, Kumari et al. found that ALKBH5 facilitated improvement of angiogenesis after acute ischemic stress by decreasing the m6A level of SPHK1 transcripts; SPHK1 regulated the phosphorylation of endothelial nitric oxide synthase (eNOS) and PI3K/AKT, two important signaling pathways for endothelium angiogenesis (101)."
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"O‐GlcNAc increases in relation to high cellular glucose uptake and oxidative stress. xref , xref , xref Acutely, O‐GlcNAc modification is thought to play a protective role for cell survival against external stress‐inducing inflammation. xref , xref However, persistent elevation of intracellular O‐GlcNAc levels can cause chronic diseases including diabetic angiopathy. xref In T2DM, impaired activation of the insulin receptor/insulin receptor substrate/PI3K (phosphatidylinositol 3‐kinase)/Akt (protein kinase B)/endothelial nitric oxide synthase (eNOS) pathway is involved in endothelial dysfunction because insulin contributes to maintenance of chronic vasodilation via NO synthesis. xref , xref , xref , xref Prior experimental studies suggest that excessive O‐GlcNAc modification that occurred in proteins of the insulin receptor/insulin receptor substrate/PI3K/Akt/eNOS pathway can reduce NO production in endothelium. xref Hyperglycemia and hexosamine activation decrease phosphorylation of eNOS by Akt. xref Specifically, O‐GlcNAc competitively inhibits the binding site of eNOS phosphorylation by Akt. xref "
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"Phosphorylation by Akt was largely confined to Ser1177, as shown by comparison of the phosphopeptide maps following 846 Current Biology, Vol 9 No 15Figure 1CaM ACaMMPK+ AktCCaonMtrol CaM+ Akt (a) (b) (c) (d) (e) Recombinant eNOS+ Akt+ AktRat eNOS 32PP-Ser1177eNOS + AMPK 32PP-Ser1177 Total eNOS proteinSer1177 Thr495OrigineNOS + CAM Ser1177 OrigineNOS + CAM + Akt Ser1177OriginEGTA CaMAktRat eNOS32PPhosphorylation of eNOS by Akt and AMPK."
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"After it was demonstrated that Akt, the downstream target of PI3K, phosphorylates eNOS and potentiates Ca and calmodulin association (Fulton et al., 1999), Haynes et al. (2000) used human umbilical vein endothelial cells (HUVECs) and EA hy926 (human endothelial-like) cells to evaluate E2’s ability to activate Akt by binding cellular membrane receptors."
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"Various stimuli such as vascular endothelial growth factor (VEGF) activate Akt in ECs, resulting in Akt dependent phosphorylation of endothelial nitric oxide synthase (eNOS) to promote NO release; NO is a critical regulator of vascular tone and blood flow, and also regulates vascular remodelling and angiogenesis."
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"TPO was found to play a crucial role in the proliferation and differentiation of precursor endothelial cells and induced PI3K/Akt-dependent phosphorylation of eNOS and release of nitric oxide, leading to dose-dependent dilation of the coronary artery and regulation of coronary blood flow."
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"Of note, Akt inhibition abrogated exercise-induced cardiac eNOS phosphorylation and NO production, while NOS inhibition by L-NAME had no impact on exercise-induced cardiac Akt phosphorylation.80 Taken together, these data suggest that exercise confers some of its effects on the heart through Akt-dependent eNOS activation and NO production."
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"It has been reported that the Akt-dependent phosphorylation of eNOS is necessary for the full activation of eNOS and endothelium-dependent vasorelaxation, and so impaired PI3K/Akt activation may have been involved in the reduced endothelium-dependent vasorelaxation ( xref ; xref )."