Methylglyoxal (MG) is highly elevated in type 2 diabetes (T2D) patients. MG covalently reacts with proteins to form non-enzymatic advanced glycation end products (AGEs), which cause cellular damage during diabetic cardiovascular complications. The T2D first-line drug therapy, metformin (MF), significantly reduces adverse diabetic endpoints more effectively than other antihyperglycemic agents. However, the exact mechanism(s) is far from well characterized. We previously discovered that MF scavenges MG to form a novel imidazoline (IMZ) metabolite, thus reducing MG-derived AGEs. We hypothesize that IMZ improves endothelial cell function and contributes to the therapeutic effects of MF. In the current studies we examined the in-vitro effects of IMZ on endothelial cell function using HUVECs cells and characterized potential signaling pathways. IMZ at physiological relevant concentrations induces the production of the endothelial derived relaxation factor, nitric oxide (NO), concomitant with an increase in the activation of eNOS. IMZ-induced NO production was blunted by pretreatment with imidazoline 1 receptor (I1R) and alpha-2 receptor (α2R) antagonists, suggesting that IMZ action is receptor mediated. We also observed that IMZ cause the activation of Akt and ERK1/2, in a concentration and time-dependent manner. IMZ-induced activation of Akt, ERK1/2, eNOS was inhibited in the presence of a PI3K inhibitor. ERK1/2 phosphorylation mediated by IMZ was also reduced in the presence of Akt1/2 specific inhibitors, suggesting that ERK1/2 might lie downstream of Akt. The effects of IMZ on angiogenesis function was examined by a tube-formation assay. IMZ treatment significantly increased tube length compared to untreated controls. Collectively, the data demonstrate that IMZ might contribute to the protective effects of metformin on endothelial cell function by activating I1R and/or α2R-Akt-ERK1/2-eNOS-NO pathway.
H. Nguyen: None.