S-Glutathionylation, eNOS leads to Uncoupling, eNOS

Oxidative stress can trigger S-glutathionylation of eNOS at cysteine residues Cys689 and Cys908, which are known to be critical for normal eNOS function (Zweier et al., 2011). S-glutathionylation directly causes eNOS uncoupling, a state in which eNOS switches from producing NO to generating superoxide, thus impairing endothelium-dependent vasodilation and contributing to endothelial dysfunction. Uncoupling of eNOS via S-glutathionylation is different from BH4-mediated eNOS uncoupling in that superoxide is produced in the reductase domain rather than the oxygenase domain and superoxide generation cannot be inhibited by L-NG-nitroarginine methyl ester (L-NAME), suggesting that S-glutathionylation occurs independent of calcium/calmodulin and heme.

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?

No study explored how much change in S-glutathionylation of eNOS is required to lead to eNOS uncoupling. One study in HUVECs showed treatment with 100nM/L Ang II increased S-glutathionylated eNOS protein expression by 1.42 fold, and was associated with an increase in superoxide generation of nearly 50% at the same dose.  DTT (which removes PR-SG residues) was shown to partially reverse this effect (Galougahi et al., 2014). Ang II and hypoxia/reoxygenation were demonstrated to be modulators of the response-response relationship between S-glutathionylation of eNOS and eNOS uncoupling as these two stressors caused a change in both key events (De Pascali et al., 2014; Galougahi et al., 2014). More experiments using other stressors or oxidants are needed to further understand of this relationship.

The evidence supporting this key event relationship are from human subjects, HAECs, BAECs, and SHR rats (Chen et al., 2010; De Pascali et al., 2014; Du et al., 2013; Jayaram et al., 2015).