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Peptide Oxidation leads to Decrease, AKT/eNOS activity
Key Event Relationship Overview
AOPs Referencing Relationship
Life Stage Applicability
|All life stages||High|
Key Event Relationship Description
Exposure to known inducers of oxidative stress causes the phosphorylation of AKT and eNOS, leading to a decrease in their activities.
Evidence Collection Strategy
Evidence Supporting this KER
Multiple experimental studies reported modulations in Akt and eNOS phosphorylation/activity following oxidative stress, thus providing strong biological plausibility for this key event relationship.
In HUVECs, peroxynitrite significantly inhibited AKT phosphorylation at Ser473 and AKT activity (Song et al., 2007, 2008; Zou et al., 2002). However, Zou et al. (2002) found that peroxynitrite increased eNOS phosphorylation at Ser1199, but decreased NO availability, suggesting eNOS phosphorylation may not depend on AKT. Treatment of BAECs with SIN-1, a source of peroxynitrite, inhibited eNOS activity by 30% and AKT/eNOS phosphorylation (Das et al., 2014).
High glucose concentrations can also inhibit AKT phosphorylation (Song et al., 2008). HUVECs treated with methylglyoxal and high concentrations of glucose exhibited reduced bradykinin-stimulated eNOS activity via Ser1177 phosphorylation (Dhar et al., 2010), while hyperglycemia inhibited eNOS activity in BAECs (Du et al., 2001). In EA.hy926 endothelial cells, methylglyoxal treatment results in reduced eNOS phosphorylation at Ser1177 (Su et al., 2013). High-fat diet-induced obesity in mice caused an increase in ROS and a reduction in AKT and eNOS phosphorylation compared to non-obese mice (Du et al., 2013).
Treatment with cigarette smoke extract (CSE) also inhibited Akt and eNOS in VEGF-stimulated HUVECs (Michaud et al., 2006). Myocardial ischemia decreased phosphorylated AKT and eNOS in spontaneously hypertension (SHR) rats compared to sham animals (Zhang et al., 2014).
Uncertainties and Inconsistencies
There are many studies examining the effect of H2O2 on AKT/eNOS phosphorylation, but there are conflicting results. Exposure to H2O2 for 30 minutes resulted in an increase in AKT/eNOS phosphorylation, but its concentration was much higher at 200 μM (Barbosa et al., 2013) compared to 5 μM in Hu et al. (2008). Another study found that treatment with 50 μM H2O2 increased eNOS phosphorylation at Ser1177 (Kumar et al., 2010). Results from studies with H2O2 as a source of ROS may not be universally applicable to this key event relationship.
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
The relationship between oxidative stress and decreased AKT/eNOS activity is supported by studies performed in humans, cows, mice and rats.
Barbosa, V.A., Luciano, T.F., Marques, S.O., Vitto, M.F., Souza, D.R., Silva, L.A., Santos, J.P.A., Moreira, J.C., Dal-Pizzol, F., Lira, F.S., et al. (2013). Acute exercise induce endothelial nitric oxide synthase phosphorylation via Akt and AMP-activated protein kinase in aorta of rats: Role of reactive oxygen species. Int. J. Cardiol. 167, 2983–2988.
Chen, X., Xu, J., Feng, Z., Fan, M., Han, J., and Yang, Z. (2010). Simvastatin combined with nifedipine enhances endothelial cell protection by inhibiting ROS generation and activating Akt phosphorylation. Acta Pharmacol. Sin. 31, 813–820.
Dhar, A., Dhar, I., Desai, K.M., and Wu, L. (2010). Methylglyoxal scavengers attenuate endothelial dysfunction induced by methylglyoxal and high concentrations of glucose. Br. J. Pharmacol. 161, 1843–1856.
Das, A., Gopalakrishnan, B., Druhan, L.J., Wang, T.-Y., De Pascali, F., Rockenbauer, A., Racoma, I., Varadharaj, S., Zweier, J.L., Cardounel, A.J., et al. (2014). Reversal of SIN-1-induced eNOS dysfunction by the spin trap, DMPO, in bovine aortic endothelial cells via eNOS phosphorylation. Br. J. Pharmacol. 171, 2321–2334.
Du, J., Fan, L.M., Mai, A., and Li, J.-M. (2013a). Crucial roles of Nox2-derived oxidative stress in deteriorating the function of insulin receptors and endothelium in dietary obesity of middle-aged mice. Br. J. Pharmacol. 170, 1064–1077.
Du, X.L., Edelstein, D., Dimmeler, S., Ju, Q., Sui, C., and Brownlee, M. (2001). Hyperglycemia inhibits endothelial nitric oxide synthase activity by posttranslational modification at the Akt site. J. Clin. Invest. 108, 1341–1348.
Guterbaum, T.J., Braunstein, T.H., Fossum, A., Holstein-Rathlou, N.-H., Torp-Pedersen, C.T., and Domínguez, H. (2013). Endothelial nitric oxide synthase phosphorylation at Threonine 495 and mitochondrial reactive oxygen species formation in response to a high H₂O₂ concentration. J. Vasc. Res. 50, 410–420.
Hu, Z., Chen, J., Wei, Q., and Xia, Y. (2008). Bidirectional actions of hydrogen peroxide on endothelial nitric-oxide synthase phosphorylation and function: co-commitment and interplay of Akt and AMPK. J. Biol. Chem. 283, 25256–25263.
Kumar, S., Sud, N., Fonseca, F.V., Hou, Y., and Black, S.M. (2010). Shear stress stimulates nitric oxide signaling in pulmonary arterial endothelial cells via a reduction in catalase activity: role of protein kinase C delta. Am. J. Physiol. Lung Cell. Mol. Physiol. 298, L105–L116.
Michaud, S.E., Dussault, S., Groleau, J., Haddad, P., and Rivard, A. (2006). Cigarette smoke exposure impairs VEGF-induced endothelial cell migration: role of NO and reactive oxygen species. J. Mol. Cell. Cardiol. 41, 275–284.
Song, P., Wu, Y., Xu, J., Xie, Z., Dong, Y., Zhang, M., and Zou, M.-H. (2007). Reactive nitrogen species induced by hyperglycemia suppresses Akt signaling and triggers apoptosis by upregulating phosphatase PTEN (phosphatase and tensin homologue deleted on chromosome 10) in an LKB1-dependent manner. Circulation 116, 1585–1595.
Song, P., Xie, Z., Wu, Y., Xu, J., Dong, Y., and Zou, M.-H. (2008). Protein kinase Czeta-dependent LKB1 serine 428 phosphorylation increases LKB1 nucleus export and apoptosis in endothelial cells. J. Biol. Chem. 283, 12446–12455.
Su, Y., Qadri, S.M., Wu, L., and Liu, L. (2013). Methylglyoxal modulates endothelial nitric oxide synthase-associated functions in EA.hy926 endothelial cells. Cardiovasc. Diabetol. 12, 134.
Zhang, W., Han, Y., Meng, G., Bai, W., Xie, L., Lu, H., Shao, Y., Wei, L., Pan, S., Zhou, S., et al. (2014). Direct renin inhibition with aliskiren protects against myocardial ischemia/reperfusion injury by activating nitric oxide synthase signaling in spontaneously hypertensive rats. J. Am. Heart Assoc. 3, e000606.
Zou, M.-H., Hou, X.-Y., Shi, C.-M., Nagata, D., Walsh, K., and Cohen, R.A. (2002). Modulation by peroxynitrite of Akt- and AMP-activated kinase-dependent Ser1179 phosphorylation of endothelial nitric oxide synthase. J. Biol. Chem. 277, 32552–32557.