| Description |
Hyperglycemia is an obvious candidate contributor in the development of endothelial dysfunction in association with insulin resistance. A great deal of evidence demonstrates that polyphenols and vitamin E can improve endothelial dysfunction, but little research has examined whether their metabolites exert protective effects on endothelial cells. In the current study, we determined the mechanisms by which metabolites can protect against high glucose-induced endothelial dysfunction in human aortic endothelial cells (HAECs). Confluent HAECs were treated with 5mM or 25mM glucose for 48h, or pretreated with 3-hydroxyphenylpropionic acid (3-HPP) at 1μM, Piceatannol (Picea) at 5μM, quercetin 3-glucuronide (Quer-3-glu) at 2μM, and 2,7,8-trimethyl-2-(beta-carboxyethyl)-6-hydroxychroman (ɤ-CEHC) at 3μM, respectively, for 24h, and then treated with high glucose (25mM) for 48h. Nitric oxide (NO) production, total and phosphorylation of endothelial NO synthase (eNOS), protein kinase B (Akt) and extracellular signal regulated kinase (ERK), and reactive oxygen species (ROS)/reactive nitrogen species (RNS) production were determined. In HAECs, insulin-stimulated NO production (59%), eNOSSer1177, and AktSer473 phosphorylation (1.3-fold and 1.5-fold, respectively) was increased (p < 0.05) in cells treated with 5mM glucose. Insulin had no stimulatory effect on NO or eNOS signaling in cells treated with 25mM glucose. However, cells pretreated for 24h with 3-HPP (1μM), Picea (5μM), Quer-3-glu (2μM), and ɤ-CEHC (3μM), respectively, and then treated with 25mM glucose for 48h, had normalized (p < 0.05) insulin-stimulated NO production, eNOSSer1177, and AktSer473 phosphorylation. There was no difference in basal NO production, eNOSSer117, AktSer473, ERKThr202/204 phosphorylation, or insulin-stimulated ERKThr202/204 phosphorylation at each treatment. ROS/RNS production was stimulated by treatment with 25mM glucose (65%, p < 0.05), and prevented when HAECs were pretreated with metabolites. In conclusion, metabolites of quercetin, resveratrol, catechin, and gamma tocopherol rescue high glucose-induced endothelial dysfunction as evidenced by increased NO production. We propose the mechanism occured through a reduction of ROS/RNS that normalized Akt-mediated eNOSSer1177 phosphorylation. |
