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Decrease, AKT/eNOS activity leads to Depletion, Nitric Oxide
Key Event Relationship Overview
AOPs Referencing Relationship
Life Stage Applicability
|All life stages||High|
Key Event Relationship Description
AKT can phosphorylate eNOS which leads to increased eNOS enzymatic activity and subsequent NO production (Dimmeler et al., 1999; Fulton et al., 1999). Inhibition of AKT attenuates eNOS phosphorylation and its activity, resulting in decreased NO bioavailability and endothelial dysfunction.
Evidence Supporting this KER
Two studies demonstrated that AKT can directly phosphorylate eNOS at Ser1177/Ser1179, leading to increased eNOS enzymatic activity and subsequent NO production in COS cells (Dimmeler et al., 1999; Fulton et al., 1999). Expressing active AKT in bovine microvascular endothelial cells also induced NO release (Fulton et al., 1999). Inhibition of Akt or a mutation of eNOS at AKT-sensitive sites attenuated eNOS phosphorylation and its activity, resulting in decreased NO bioavailability and endothelial dysfunction (Dimmeler et al., 1999; Fulton et al., 1999; Uruno et al., 2005). Treatment of BAECs with SIN-1 resulted in a reduction in both eNOS activity and NO production (Das et al., 2014). Cigarette smoke extract (CSE) treatment inhibited AKT and eNOS and NO release in VEGF-stimulated HUVECs (Michaud et al., 2006), and methylglyoxal and high glucose reduced eNOS bradykinin-stimulated eNOS activity and NO production in HUVECs (Dhar et al., 2010). Overall, the biological plausibility for decreased AKT/eNOS activity leading to NO depletion is strong.
Uncertainties and Inconsistencies
In the context of this AOP, decreased activity of AKT is likely due to proteasomal degradation following exposure to a (oxidative) stressor (Abdehghany et al. 2017). However, decreased eNOS activity could be due to multiple causes, highlighted in this AOP. Firstly, if AKT expression levels are reduced, it follows that eNOS phosphorylation will be reduced. Secondly, similar to AKT, eNOS itself has been shown to be susceptible to proteasomal degradation (Abdehghany et al. 2017). Thirdly, depletion of BH4 and/or S-glutathionylation has been shown to uncouple eNOS, leading to reduced NO levels and increased superoxide levels. The relative contribution of each of these eNOS perturbation routes to NO depletion is currently unknown.
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
The relationship between decreased AKT/eNOS activity and NO depletion is supported by studies performed in humans, cows, and rats.
AbdelGhany, T., Ismail, R., Elmahdy, M., Mansoor F, Zweier J, Lowe, F., and Zweier, JL. (2017). Cigarette Smoke Constituents Cause Endothelial Nitric Oxide Synthase Dysfunction and Uncoupling due to Depletion of Tetrahydrobiopterin with Degradation of GTP Cyclohydrolase. Nitric Oxide (Under review).
Choi, Y.-J., Yoon, Y., Lee, K.-Y., Hien, T.T., Kang, K.W., Kim, K.-C., Lee, J., Lee, M.-Y., Lee, S.M., Kang, D.-H., et al. (2014). Uric acid induces endothelial dysfunction by vascular insulin resistance associated with the impairment of nitric oxide synthesis. FASEB J. 28, 3197–3204.
Choi, Y.-J., Yoon, Y., Lee, K.-Y., Kang, Y.-P., Lim, D.K., Kwon, S.W., Kang, K.-W., Lee, S.-M., and Lee, B.-H. (2015). Orotic Acid Induces Hypertension Associated with Impaired Endothelial Nitric Oxide Synthesis. Toxicol. Sci. 144, 307–317.
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.
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.
Dimmeler, S., Fleming, I., Fisslthaler, B., Hermann, C., Busse, R., and Zeiher, A.M. (1999). Activation of nitric oxide synthase in endothelial cells by Akt-dependent phosphorylation. Nature 399, 601–605.
Dumitrescu, C., Biondi, R., Xia, Y., Cardounel, A.J., Druhan, L.J., Ambrosio, G., and Zweier, J.L. (2007). Myocardial ischemia results in tetrahydrobiopterin (BH4) oxidation with impaired endothelial function ameliorated by BH4. Proc. Natl. Acad. Sci. U. S. A. 104, 15081–15086.
Fulton, D., Gratton, J.P., McCabe, T.J., Fontana, J., Fujio, Y., Walsh, K., Franke, T.F., Papapetropoulos, A., and Sessa, W.C. (1999). Regulation of endothelium-derived nitric oxide production by the protein kinase Akt. Nature 399, 597–601.
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.
Uruno, A., Sugawara, A., Kanatsuka, H., Kagechika, H., Saito, A., Sato, K., Kudo, M., Takeuchi, K., and Ito, S. (2005). Upregulation of nitric oxide production in vascular endothelial cells by all-trans retinoic acid through the phosphoinositide 3-kinase/Akt pathway. Circulation 112, 727–736.
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.