AUTHOR=Sonmez Muhammed Ikbal , Shahzadi Andleeb , Kose Cagla , Sonmez Haktan , Ozyazgan Sibel , Akkan Ahmet Gokhan 

TITLE=Effect of sulfasalazine on endothelium-dependent vascular response by the activation of Nrf2 signalling pathway

JOURNAL=Frontiers in Pharmacology

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2022.979300

DOI=10.3389/fphar.2022.979300

ISSN=1663-9812

ABSTRACT=<p><bold>Background:</bold> Diabetes mellitus leads to endothelial dysfunction and accumulation of oxygen radicals. Sulfasalazine-induced Nrf2 activation reduces oxidative stress in vessels. Thus, in the present study, we investigated the effects of sulfasalazine on endothelial dysfunction induced by high glucose. We also ascribed the underlying mechanism involved in glucose-induced endothelial dysfunction.</p><p><bold>Methods:</bold> For this experiment we used 80 Wistar Albino rats thoracic aorta to calculate the dose response curve of noradrenaline and acetylcholine. Vessels were incubated in normal and high glucose for 2 h. To investigate glucose and sulfasalazine effects the vessels of the high glucose group were pre-treated with sulfasalazine (300 mM), JNK inhibitor (SP600125), and ERK inhibitor (U0126) for 30 min. The dose response curve was calculated through organ bath. The eNOS, TAS, TOS, and HO-1 levels were estimated by commercially available ELISA kits.</p><p><bold>Results:</bold> In the high glucose group, the E<sub>max</sub> for contraction was significantly higher (<italic>p</italic> &lt; 0.001), and E<sub>max</sub> for relaxation was lower than that of control. These functional changes were parallel with the low levels of eNOS (<italic>p</italic> &lt; 0.05). High glucose vessel treated with sulfasalazine showed low E<sub>max</sub> value for contraction (<italic>p</italic> &lt; 0.001) however, the E<sub>max</sub> for relaxation was significantly high (<italic>p</italic> &lt; 0.001) when compared to high glucose group. In the JNK group, E<sub>max</sub> for contraction and relaxation was inhibited (<italic>p</italic> &lt; 0.001) compared to sulfasalazine treated vessels. HO—1 enzyme levels were significantly low (<italic>p</italic> &lt; 0.01) with sulfasalazine but higher with ERK inhibitor (<italic>p</italic> &lt; 0.05).</p><p><bold>Conclusion:</bold> High glucose induced endothelial dysfunction and sulfasalazine reduced damage in high glucose vessels by activating eNOS, antioxidant effect through HO-1 enzymes and particularly inducing Nrf2 <italic>via</italic> the ERK and JNK pathways.</p>