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

Abstract

Background: 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.Methods: 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.Results: In the high glucose group, the Emax for contraction was significantly higher (p < 0.001), and Emax for relaxation was lower than that of control. These functional changes were parallel with the low levels of eNOS (p < 0.05). High glucose vessel treated with sulfasalazine showed low Emax value for contraction (p < 0.001) however, the Emax for relaxation was significantly high (p < 0.001) when compared to high glucose group. In the JNK group, Emax for contraction and relaxation was inhibited (p < 0.001) compared to sulfasalazine treated vessels. HO—1 enzyme levels were significantly low (p < 0.01) with sulfasalazine but higher with ERK inhibitor (p < 0.05).Conclusion: 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 via the ERK and JNK pathways.

New Ideas for the Prevention and Treatment of Preeclampsia and Their Molecular Inspirations

“…This drug reduces high blood pressure in pregnant mice developing preeclampsia caused by injection of a nitric oxide synthase antagonist, i.e., L-NAME [120]. This suggests that sulfasalazine may prevent the endothelial dysfunction least by upregulating the activity of eNOS and the production of vasodilatory factors such as nitric oxide [121]. Sulfasalazine may exert its positive influence on vasoactivity of maternal vessels through its potential to increase placental PlGF production and reduce the secretion of sFlt1 in an epidermal growth factor receptor-dependent manner [122][123][124].…”

Ginsenoside Rk1 improves endothelial function in diabetes through activating peroxisome proliferator-activated receptors

“…[25][26][27] A few studies have applied higher concentrations of glucose, 40 mM or 44 mM HG for culturing RAECs and rat aortas. 28,29 There is a study limitation that 30 mM HG should be used to stimulate RAECs so that the findings will be more physiologically relevant. Oral administration of ginsenoside Rk1 for 4 weeks improved hyperglycemia and high blood pressure in DIO mice.…”