The Non-Nutritive Sweetner Erythritol Adversely Affects Brain Microvascular Endothelial Cell Function.

Abstract

The experimental aim of this study was to determine, in vitro, the effect of the non-nutritive sweetener erythritol on brain microvascular endothelial cell oxidative stress, nitric oxide (NO) and endothelin (ET)-1 production, as well as tissue-type plasminogen activator (t-PA) release. Human cerebral microvascular endothelial cells (hCMECs) were cultured and treated with 6 mM of erythritol, equivalent to a typical amount of erythritol [30g] in an artificially sweetened beverage, for 3 hr. Intracellular reactive oxygen species (ROS) production was significantly higher in hCMECs treated with erythritol (204±32% vs 105±4%) as well as expression of antioxidant proteins superoxide dismutase-1 (332.1±16.2 vs 214.9±4.7 AU; P=0.002) and catalase (30.9±0.3 vs 24.4±0.9 AU; P=0.002). Although endothelial nitric oxide synthase (eNOS) expression was not significantly altered (102.8±21.4 vs 99.0±19.9 AU); expression of p-eNOS (Ser1177) was lower (52.1± 2.1 vs 77.3±9.1 AU; P<0.001) and p-eNOS (Thr495) higher (63.4±8.0 vs 45.6±6.9 AU; P=0.006) in hCMECs treated with erythritol. Cell expression of Big ET-1 was also higher in erythritol-treated cells (56.4±9.8 vs 40.9±6.5 AU; P=0.02). Consequently, endothelial NO production was significantly lower (5.8±0.8 vs 7.3±0.7 μmol/L) and ET-1 production significantly higher (34.6±2.3 vs 26.9±1.5 pg/mL) in response to erythritol. t-PA release in response to thrombin was significantly blunted in erythritol treated (from 87.4±6.3 to 87.6±8.3 pg/mL) versus untreated (90.1±5.5 to 110.2±6.4 pg/mL) hCMECs. In summary, erythritol adversely affects oxidative stress, NO production, ET-1 production and t-PA release in brain microvascular endothelial cells; potentially contributing to the increased risk of ischemic stroke associated with erythritol.