Alagebrium targets the miR-27b/TSP-1 signaling pathway to rescue N^?-carboxymethyl-lysine-induced endothelial dysfunction.

ABSTRACT: N^?-carboxymethyl-lysine (CML), a major isoform of advanced glycation end products (AGEs), plays a crucial role in the functional damage of diabetes mellitus. However, it is not clear whether ALT-711 (alagebrium), an inhibitor of AGEs, is capable to rescue CML-induced poor angiogenesis, as well as the underlying mechanism. MicroRNA-27b (miR-27b) promotes angiogenesis through down-regulation of anti-angiogenic protein thrombospondin-1 (TSP-1). Here, we used diabetic mice with hindlimb ischemia to investigate whether miR-27b/TSP-1 signaling is involved in the pathology of critical limb ischemia (CLI) in diabetes mellitus. We additionally examined the effect of ALT-711 on the tube formation of endothelial cells treated with CML-BSA. Compared with control group, the lower blood flow recovery was observed in the ischemic lower limbs of diabetic mice, with decreased expression of vascular endothelial growth factor (VEGF) and miR-27b and increased TSP-1 expression. CML-BSA reduced the tube formation ability of endothelial cells, decreased VEGF and miR-27b expression, and increased TSP-1 expression, whereas this trend was reversed by ALT-711. The miR-27b mimic promoted tube formation, increased VEGF expression, and decreased TSP-1 expression, whereas these effects were abolished by TSP-1 overexpression. Moreover, miR-27b silencing suppressed ALT-711-induced promotion of tube formation under CML-BSA treatment, with reduced VEGF and augmented TSP-1 expression. Taken together, the present study demonstrated that ALT-711 can rescue CML-induced functional angiogenesis damage via miR-27b/TSP-1 signaling cascades. These results indicate new therapeutic strategies for diabetes patients with CLI.

SUBMITTER: Chen Y 

PROVIDER: S-EPMC6456531 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature