Relationship:992

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Key Event Relationship Overview

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Description of Relationship

Upstream Event Downstream Event/Outcome
Oxidative Stress, Increase Akt/eNOS activity, Decrease

AOPs Referencing Relationship

AOP Name Type of Relationship Weight of Evidence Quantitative Understanding
Oxidative Stress Leading to Arterial Stiffness Directly Leads to Strong Moderate

Taxonomic Applicability

Name Scientific Name Evidence Links
Homo sapiens Homo sapiens Strong NCBI
Bos taurus Bos taurus Strong NCBI
Mus musculus Mus musculus Weak NCBI
Rattus norvegicus Rattus norvegicus Weak NCBI

How Does This Key Event Relationship Work

Exposure to known inducers of oxidative stress causes the phosphorylation of Akt and eNOS, leading to a decrease in their activities.

Weight of Evidence

Biological Plausibility

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).

Empirical Support for Linkage

Include consideration of temporal concordance here

There is moderate empirical support for this link as eNOS activity and ROS were modulated by several stressors. Treatment with 30 μM methylglyoxal (MG) and 25 mM glucose (HG) for 24 hours caused an increase in ROS (control: 0.77, MG: 1.2, HG: 1) and a decrease in eNOS activity (control: 100%, MG: 55%, HG: 66%) in HUVECs (Dhar et al., 2010). SIN-1 treatment for two hours increased ROS (100% to 290%) and decreased eNOS activity (100% to 70%) (Das et al., 2014). An increase in ROS and decrease in eNOS activity was observed following treatment with 100 μmol/L H2O2 (Chen et al., 2010). Another study showed that 5 μM H2O2 treatment initially increased eNOS Ser1179 phosphorylation and activity but after the peak increase at 30 minutes, eNOS Ser1179 phosphorylation dramatically decreased (Hu et al., 2008). A similar trend was observed for Akt phosphorylation. Treatment with 100 μM/L H2O2 for 30 minutes inhibited eNOS expression (Chen et al., 2010), assuming that eNOS expression translates to eNOS activity. Treatment with H2O2 (400 uM, 30 min) increased eNOS phosphorylation at the inhibitory site Thr495, suggesting eNOS activity increased (Guterbaum, 2013).

Uncertainties or 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.

Quantitative Understanding of the Linkage

Is it known how much change in the first event is needed to impact the second? Are there known modulators of the response-response relationships? Are there models or extrapolation approaches that help describe those relationships?

Dhar et al. showed that an increase of >30% in ROS from high glucose and methylglyoxal was able to decrease eNOS activity, while Das et al. showed a three-fold increase in ROS lead to a 30% reduction in eNOS activity. SIN-1, high glucose, methylglyoxal and H2O2 were demonstrated to cause a modulation in both key events at the same time.

Evidence Supporting Taxonomic Applicability

The relationship between oxidative stress and decreased Akt/eNOS activity is supported by studies performed in humans, cows, mice and rats.

References

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.